Presentation Abstracts - XIXth World Congress of Psychiatric Genetics

Table of Contents
EDUCATIONAL SESSION ABSTRACTS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
PLENARY ABSTRACTS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
SYMPOSIA ABSTRACTS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
INDIVIDUAL ORAL PRESENTATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
POSTER SESSION I ABSTRACTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
GENOMICS (GWAS, SEQUENCING) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
POSTER SESSION II ABSTRACTS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
ELSI, COUNSELING, AND GENETIC TESTING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
EPIGENOMICS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
PHENOTYPES & ENDOPHENOTYPES. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
POSTER SESSION III ABSTRACTS: SPECIAL SESSION ON SUBSTANCE ABUSE GENETICS . . . . . . . . . . . . . . . . . 144
POSTER SESSION IV ABSTRACTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
STATISTICAL GENETICS, GENETIC EPIDEMIOLOGY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
FUNCTIONAL GENOMICS & MODEL ORGANISMS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
OTHER. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186
PHARMACOGENOMICS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
AUTHOR INDEX. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
LEGEND
E-EDUCATIONAL SESSION
P-PLENARY
S-SYMPOSIA
OPS-ORAL PRESENTATIONS
PP-POSTER PRESENTATIONS
ECIP - EARLY CAREER INVESTIGATOR’S PROGRAM (ORAL AND POSTER AWARD FINALISTS)
1

EDUCATIONAL
SESSION
ABSTRACTS
2

RECRUITMENT OF SUBJECTS: LESSONS LEARNED OVER
25 YEARS
L. Kassem*(1), D. Kazuba(1), C. Drain(2), C. Fisher(3), E.
Murphy(1)
1. NIMH/NIH 2. Washington University School of Medicine 3.
Indiana University School of Medicine
*kasseml@mail.nih.gov
This educational session will discuss subject recruitment and
retention for genetic studies. The correlation between the success of a
study and the strength and skill of its recruitment team has been
shown to be consistently high. Members of the panel have been
involved in subject recruitment for 25 years, and their collective and
diverse experience demonstrates that success requires a delicate
balance between simplicity and complexity, learned techniques and
art. This is particularly the case where studies are focused on diverse
or culturally-sensitive and unique populations, and where the advent
of novel advertising and screening approaches needs to be cognizant
of current legal, ethical and other sensitivities. The panel will briefly
review recruitment history, variables contributing to success and
approaches to be avoided.
The proposed panel of speakers includes:
Caroline Drain, of Washington University School of Medicine, will
discuss advertisement methods and report on the best and worst
approaches. In this section, “spreading the word” will be addressed
specifically the panel will review the preparation of advertisement
material to be used in different forms of media (e.g. fliers,
newspapers, use of websites and radio advertisements). We will
present examples of successful as well as unsuccessful
advertisements, and we will discuss the art of tailoring
advertisements for different populations. Data demonstrating the
success of different forms of advertising will be presented.
Carrie Fisher, of Indiana University School of Medicine, will review
efficient methods for obtaining informed consent. Here the panel will
examine the meaning of “informed” and “consent”. The discussion
will be aimed at identifying “subject friendly” methods for obtaining
informed consent. For example, is it best to obtain consent in person,
by mail or over the telephone? Data comparing the return rate of
consent forms from the different approaches will be presented.
Diane Kazuba, of the National Institutes of Mental Health/NIH, will
discuss the construction of screening questionnaires and the
conducting of the screening interviews - the screening interview is
our subject’s first interaction with us. In this section, the screening
process, starting with the construction of the interview and ending
with techniques for ensuring our subjects’ comfort with the process
and willingness to cooperate, will be reviewed. Data reflecting the
difference between the number of subjects screened and the number
of subjects actually recruited will be presented a discussion on how to
decrease that difference will follow.
The introduction and discussion will be lead by Layla Kassem who
will also review issues, and resultant approaches, arising in the
recruitment of diverse (and culturally-sensitive and unique)
populations. At the end of the session, it is hoped that participants
will have a better understanding of effective and efficient
advertisement methods, the construction of screening tools, informed
consent, and the recruitment of diverse populations.
3
WHAT CAN WE LEARN FROM LONGITUDINAL STUDY
DESIGN? EXPERIENCES AND STUDIES OF INDIVIDUALS
AT GENETIC HIGH-RISK FOR BIPOLAR DISORDER
EARLY CLINICAL STAGES OF BIPOLAR DISORDER:
FINDINGS FROM A LONGITUDINAL STUDY OF
GENETICALLY AT-RISK OFFSPRING
A. Duffy*(1), J. Horrocks(2), U. Lewitzka(3), M. Alda(1), S.
Doucette(1), P. Grof(4)
1. Dalhousie University 2. Guelph University 3. University Hospital
Dresden 4. University of Toronto
*anne.duffy@dal.ca
Introduction: There is a relative lack of information regarding the
early natural history of bipolar disorder, compared to our
understanding of the course of established (full-blown) illness. Given
the substantial genetic contribution to bipolar disorder, longitudinal
study of the offspring of affected parents represents an important
research strategy to map the trajectory into illness and study
intermediate phenotypes and causal pathways, while minimizing the
effect of the burden of the illness.
Methodology: Eligible probands were identified from participation
in neurobiological studies which confirmed a diagnosis of BDI based
on SADS-L research interviews by pairs of research
psychiatrists. Blind consensus diagnostic reviews confirmed DSM-
IV diagnosis using research interviews and reviewing all available
clinical and treatment history. Lithium response (LiR) or nonresponse
(LiNR) was determined in accordance with published
research protocol. Agreeable probands and any of their affected first
degree relatives (BDI, II, recurrent MDD) with children in the age
range of 7-25 years were approached for the study. Families were
excluded if the other biological parent had a lifetime history of a
major psychiatric disorder. A comparison group of families were
included in which both parents had no lifetime major psychiatric
disorder based on SADS-L interviews or ongoing acute or chronic
major medical illness.All assenting/consenting children of eligible
families and a parent were interviewed by a research psychiatrist
using KSADS-PL format, blind to family affiliation and study
group. Lifetime diagnoses were made using best-estimate procedures
as described above.
Results: This analysis includes 108 high-risk (HR) families and 55
low-risk (C) families with 216 and 87 offspring, respectively. HR
offspring had higher rates of lifetime psychopathology compared to C
offspring specifically, 69.9% vs 19.5% Axis I disorders, 39.3% vs
3.4% Depressive Disorders and 14.9% vs 1.1% BD, respectively.
In separate analyses, the age-corrected morbid risk of mood disorder,
given a prior history of anxiety disorder was 85% compared to 40%
in those without a prior history of an anxiety disorder (hazard of 2.6
CI=1.59-4.25). Using Cox proportional hazards models with timevarying
covariates, the risk of MDD was multiplied by a factor of
1.96 having experienced SUD (p=.039, 95% CI=1.03, 3.72). The risk
of SUD was multiplied by a factor of 2.04 having experienced MDD
(p=.052, 95% CI=0.99, 4.18). The risk of BD was multiplied by a
factor of 2.66 once subjects had experienced SUD (p=.010, 95%
CI=1.26, 5.61). The temporal sequence of psychopathology in those
offspring who met lifetime criteria for BD I or II disorder followed a
predictable pattern (see figure 1).
Conclusions: A developmental approach appears important to
refining the diagnosis of BD in children and youth at genetic
risk. Data from the present high-risk longitudinal study suggests
evidence of clinical staging. This has implications for both
intervention/prevention studies and studies of genetically sensitive
intermediate pathways.
H.C. PRECHTER LONGITUDINAL STUDY OF BIPOLAR

DISORDER: BASELINE DESCRIPTIVE ANALYSIS OF
INDIVIDUALS WITH AND WITHOUT BIPOLAR DISORDER
M. McInnis*
University of Michigan
*mmcinnis@umich.edu
Introduction: The HC Prechter Longitudinal Study of Bipolar
Disorder is an open cohort study designed to gather detailed clinical
and biological data for research on the course and outcome of bipolar
individuals.
Methodology: Diagnoses are made with the DIGS. Current
symptoms of depression and mania are assessed using the Hamilton
Depression Rating Scale and the Young Mania Rating Scale.
Personality parameters are estimated by the NEO-PI. Self-report
instruments are used to capture histories of social and family support,
life events and history of abuse as well as sleep parameters and
patterns of circadian rhythms. Neuropsychological measures
determine domains of functioning, including attention, memory, and
executive functioning. Biological materials including DNA, salivary
cortisol, and plasma for biomarkers are collected. The central
hypothesis is that response and illness patterns will be predicted from
the clinical, psychological, environmental, and genetic parameters.
The longitudinal nature of the study will allow for both state and trait
based analyses.
Results: Currently 624 participants are enrolled. The average age of
onset for the bipolar I and II individuals is 19 years. The average age
at interview for bipolar individuals is 40 years versus 32 years for
controls. Recent findings show differences in cognitive functioning
between individuals with and without bipolar disorder, as well as
differential patterns in the depressed and hypomanic bipolar states. A
lower socioeconomic burden of illness (disability) is associated with
lower impact on cognitive and emotional factors.
Conclusions: This research supports further pursuit of disease traits
through longitudinal study designs that combine cognitive,
behavioral, social, environmental, and biological factors, which is the
basis of the H.C. Prechter Longitudinal Study. Building a
longitudinal database with ongoing and additional studies with an
open cohort that can be engaged in further research is key for the
future of translational research in mood disorders.
4
IMPAIRED INFERIOR FRONTAL GYRUS RESPONSE TO
AN EMOTIONAL INHIBITION TASK IN YOUNG FIRST-
DEGREE RELATIVES OF BIPOLAR DISORDER PATIENTS
COMPARED TO CONTROLS
P. Mitchell*(1, 2), G. Roberts(1, 2), M. Green(1, 2), M.
Breakspear(1, 2, 3), C. McCormack(1, 2), A. Frankland(1, 2), A.
Wright(1, 2), C. McCue(1, 2), D. Hadzi-Pavlovic(1, 2), F. Levy(1),
B. Lino(1, 2), R. Lenroot(1, ), J. Corry(1, 2)
1. University of New South Wales 2. Black Dog Institute 3.
Queensland Institute of Medical Research
*phil.mitchell@unsw.edu.au
Introduction: Current evidence for cognitive and neuroanatomical
correlates of the genetic predisposition to bipolar disorder implicate
frontal cortical, and sub-cortical striatal and limbic systems involved
in the cognitive control of emotion. However, there have been few
functional imaging studies of individuals at high genetic risk for
bipolar disorder. We examined neural activity associated with the
inhibition of emotional material in young people at-risk for
developing bipolar disorder, using an emotional inhibition paradigm,
with the hypothesis that emotional material would impede the
efficiency of cortical inhibitory networks.
Methodology: Forty-eight genetically defined "high-risk”
individuals, aged between 18 and 30 years, with at least one firstdegree
relative with a diagnosis of bipolar disorder, and 49 healthy
comparison participants performed a facial emotion go/no-go task
during the acquisition of functional magnetic resonance imaging data.
Results: All participants exceeded 75% accuracy. Whole brain
analyses, corrected for family-wise error, revealed that at-risk
participants demonstrated a highly specific and significant lack of
recruitment of the inferior frontal gyrus when inhibiting fearful faces,
compared to healthy controls (p=0.027, FWE corrected).
Conclusions: This finding suggests a dysregulated frontal inhibitory
network for the inhibition of threatening emotion which may
represent a neurocognitive endophenotype for bipolar disorder. This
extends previous reports that the inferior frontal gyrus is under-active
in patients with established bipolar disorder compared to normal
controls by suggesting that it is also present in those genetically atrisk
of the disorder.

CHILDHOOD DISORDERS PREDICT ADOLESCENT ONSET
MOOD DISORDER IN FAMILIES WITH A BIPOLAR
PROBAND
J. Nurnberger *(1), M. McInnis(2), H. Wilcox(3), A. Glowinski(4),
P. Mitchell(5), E. Gershon(6), W. Berrettini(7), G. Laite(1), R.
Schweitzer(1), X. Cai(8), F. Azzouz(1), H. Liu(1), M. Kamali(2)
1. Indiana University 2. University of Michigan 3. Johns Hopkins
University 4. Washington University 5. University of New South
Wales 6. University of Chicago 7. University of Pennsylvania 8.
University of Iowa
*jnurnber@iupui.edu
Introduction: The childhood precursors of adult bipolar disorder
(BP) are still a matter of controversy. Our objective was to report the
lifetime prevalence and early clinical predictors of psychiatric
disorders in offspring from families of probands with DSM-IV
Bipolar Disorder compared to offspring of controls. We are carrying
out a longitudinal, prospective study of subjects at risk for BP and
related disorders. We report initial (cross-sectional and retrospective)
diagnostic and clinical characteristics following best estimate
procedures.
Methodology: Assessment was performed at four university medical
centers in the U.S. between June 2006 and September 2009.
Participants were offspring ages 12-21 in families with a BP proband
(n=141, designated as cases) as well as similarly aged offspring of
control parents (n=91). The main outcome measure was lifetime
DSM IV diagnosis of major affective disorder (BPI, SABP, BPII, or
Major Depression) as determined by a best estimate diagnostic
process that included information from the K-SADS-BP on both
child and parent and also medical records.
Results: At an average age of 17, cases showed 23.4% lifetime
prevalence of major affective disorder compared to 4.4% in controls
(p = 0.002, adjusting for age, gender, ethnicity, and correlation
between siblings). Prevalence of bipolar disorder in cases was 8.5%
vs. 0% in controls (adjusted p = 0.007). No significant difference was
seen in prevalence of other affective, anxiety, disruptive behavior
disorders, or substance use disorders. Among case subjects
manifesting major affective disorder (n=33), there was an increased
risk for anxiety and externalizing disorders in comparison to cases
without mood disorder. In cases but not controls, a childhood
diagnosis of an anxiety disorder (Relative Risk (RR) = 2.6 (1.1 –
6.3), p = 0.039) or an externalizing disorder (RR = 3.6 (1.4 – 9.0), p =
0.007) was predictive of later onset of major affective disorder.
Conclusions: Childhood anxiety and externalizing diagnoses predict
major affective illness in adolescent offspring in families with BP
probands.
5
TRANSLATIONAL RESEARCH IN ANXIETY: HOW
ANIMAL-BASED MODELS CAN COMPLEMENT HUMAN
GENETICS
EPIGENETIC MODIFICATION OF THE STRONG GENETIC
PREDISPOSITION TOWARDS ANXIETY-RELATED
BEHAVIOR IN PSYCHOPATHOLOGICAL HAB MICE
R. Landgraf*, P. Markt, C. Avrabos, R. Naik, M. Eder, L. Czibere
Max Planck Institute of Psychiatry
*landgraf@mpipsykl.mpg.de
Introduction: To mimic clinically relevant endophenotypes, we
created extremes in the genetic predisposition to anxiety-related
behavior by inbreeding CD-1 mice for either high (HAB),
intermediate (NAB) or low (LAB) anxiety for >40 generations. This
intra-strain, tri-directional approach provides the advantage that
selection pressure is exerted on anxiety only, while maintaining a
high degree of similarity in non-selected traits. Furthermore, due to
their seemingly rigid predisposition, HAB/NAB/LAB mice are
virtually independent of confounding variables such as uterine
environment (embryo transfer), maternal care (cross-fostering), sex
and age. Importantly, trait anxiety is associated with depression-like
behaviors, resembling clinical comorbidity.
Methodology: Chip technologies for expression profiling and
genotyping sequencing allele-specific transcription gene reporter
assays association studies.
Results: As exemplarily shown in a number of candidate genes (e.g.,
Avp, Tmem132d, Npsr1, Crhr1, cathepsin), polymorphisms differing
between HAB and LAB do not only underlie differences in
expression, but are also associated with the anxiety phenotype in a
freely segregating F2 panel, suggesting a causal contribution. Despite
the robust genetic predisposition, environmental stimuli were found
to shift both HAB (enriched environment) and LAB (unpredictable
chronic mild stress) towards NAB, highlighting an efficient
phenotypic rescue. In the amygdala of HAB mice, correlates of that
rescue include (i) neuronal activity, which accompanies the
phenotypic shift, as well as (ii) epigenetic modifications with
expression of the Crhr1 gene being reduced and its methylation status
being altered upon enriched environment.
Conclusions: This animal model thus offers the opportunity to study
possible interactions between genetic predisposition and epigenetic
modifications in more detail, both genome-wide and at single gene
level.

TMEM132D: A NEW CANDIDATE FOR ANXIETY
PHENOTYPES - EVIDENCE FROM HUMAN AND MOUSE
STUDIES
A. Erhardt*
Max Planck Institute for Psychiatry
*erhardt@mpipsykl.mpg.de
Introduction: Family and twin studies indicate an estimated
heritability for anxiety and panic disorders up to 30-40%. In contrast
to candidate gene studies, genome-wide association investigations
present an unbiased approach and are helpful to reveal novel
pathological pathways in complex diseases.
Methodology: We performed a whole-genome association study in
three different German samples with panic disorder patients and
healthy controls (909 cases and 915 controls).
Results: SNPs in TMEM132D were found to be associated with
panic disorder, with a two SNP haplotype associated in each of three
samples in the same direction, with a p-value of 1.2e-7in the
combined sample. Independent SNPs in this gene were also
associated with the severity of anxiety symptoms, in patients affected
by panic disorder or panic attacks as well as patients suffering from
unipolar depression. Risk genotypes for panic disorder were
associated with higher TMEM132D mRNA expression levels in the
frontal cortex. In parallel, using a mouse model of extremes in trait
anxiety, we could further demonstrate that anxiety-related behavior
was positively correlated with Tmem132d mRNA expression in the
anterior cingulate cortex, central to the processing of anxiety/fearrelated
stimuli, and that in this animal model a Tmem132d SNP is
associated with anxiety-related behavior in an F2 panel. Further
validation studies using next-generation sequencing revealed high
number of rare variants in this gene. Additionally, behavioural and
molecular phenotyping in the mouse knock-out model is ongoing to
investigate, how TMEM132D is implicated in the regulation of
anxiety-related behaviour.
Conclusions: TMEM132D is an important new candidate gene for
panic disorder as well as more generally for anxiety-related behavior.
6
MICRORNA EXPRESSION PATTERNS IN A MOUSE
MODEL OF ANXIETY
T. Sipilä(1,2,3), K. Icay(1,2), J. Juhila(1,2,4), P. Ellonen(4), D.
Greco(5), I. Hovatta*(1,2,3,4)
1. Research Programs Unit, Molecular Neurology, Biomedicum-
Helsinki, University of Helsinki 2. Department of Medical Genetics,
Haartman Institute, University of Helsinki 3. Department of Mental
Health and Substance Abuse Services, National Institute for Health
and Welfare 4. Institute of Molecular Medicine Finland (FIMM),
University of Helsinki 5. Department of Bioscience and Nutrition,
Karolinska Institutet
*iiris.hovatta@helsinki.fi
Introduction: MicroRNAs (miRNAs) are small regulatory molecules
that suppress mRNA activity. They have been isolated and
characterized in all organisms and tissues, and in mammalian brain
they are shown to be involved in neuronal differentiation and
synaptic plasticity. Recent evidence points at the involvement of
miRNA expression differences in neuropsychiatric diseases. Our aim
was to identify miRNAs that participate in the regulation of anxietylike
behavior in a mouse model. This model consists of six inbred
mouse strains that differ in their innate anxiety like behavior: A/J,
DBA/2J, 129S1/SvImJ, C3H/HeJ, C57BL/6J, and FVB/NJ. We have
earlier carried out gene expression profiling in refined brain regions
of these strains and identified gene expression differences underlying
anxiety-like behavior.
Methodology: We have setup a miRNA-seq protocol for quantitative
miRNA expression analysis from mouse brain regions. Using this
approach, we carried out miRNA expression profiling from three
brain regions playing a key role in the regulation of anxiety: frontal
cortex, hippocampus and hypothalamus. We correlated the miRNA
expression profiles with anxiety-like behavior, measured by the open
field and light dark box tests, across the six strains.
Results: We identified 53 miRNAs with expression levels that
correlate with anxiety-like behavior. Using the miRWalk tool, which
combines information from several target prediction algorithms, we
predicted target genes for each differentially expressed miRNA. To
assess the putative biological functions of the differentially expressed
miRNAs and their predicted targets, we carried out pathway analyses
with the Ingenuity Pathways Analysis tool. Several differentially
expressed miRNAs were predicted to regulate target genes within the
same biological pathways.
Conclusions: Identification of miRNAs with expression pattern
correlating with anxiety-like behavior enables formation of specific
testable hypotheses regarding the gene regulatory networks
underlying anxiety. These hypotheses can be tested by functional
studies in mouse models or in human anxiety disorder cohorts.

NEURAL CORRELATES OF GENETICALLY-DRIVEN
STRAIN DIFFERENCES IN FEAR.
A. Holmes*
NIAAA
*holmesan@mail.nih.gov
Introduction: Only a fraction of individual exposed to severe
psychological trauma will meet diagnostic criteria for a clinical
anxiety disorder. Risk likely results from genetic influences and gene
x environment interactions that drive functional alterations in neural
circuits regulating emotion. One approach to disentangle these risk
factors is to identify strain, subpopulation or selectively bred rodent
lines that show excessive fear after a trauma such as fear
conditioning.
Methodology: This presentation will discuss multi-level analysis of
two isogenic mouse strains (S1 and B6) exhibiting divergent fear
extinction and corticoamygdala circuit function.
Results: Results will show that S1 exhibited deficient extinction,
overgeneralized fear to ambiguous cues and failed to effectively use
safety cues to inhibit fear. Fear abnormalities in S1 were associated
with autonomic disturbances and HPA-axis abnormalities, and were
fully rescued by chronic treatment with the anti-anxiety medication,
fluoxetine. Within the fear-circuit, S1 had enlarged dendritic arbors
in basolateral amygdala neurons in S1, but normal dendritic
arborization in infralimbic and prelimbic cortices. Moreover,
multichannel unit recording revealed aberrant extinction-related
infralimbic cortex single-unit activity and uncoupling of neuronal
bursting from extinction, in S1.
Conclusions: Together, these data provide novel, convergent insights
into the factors underlying genetically-driven differences in fear
regulation.
7
FROM GENE TO DRUG RESPONSE: MULTI-METHOD
APPROACH TO THE PHARMACOGENOMICS OF
RESPONSE TO ANTIDEPRESSANTS
FROM GENE TO DRUG RESPONSE: MAKING MORE OF
GENOME-WIDE PHARMACOGENETIC DATA
R. Uher*(1), K. Tansey(1), M. Guipponi(2), N. Perroud(2), A.
Malafosse(2), X. Hu(3), G. Lewis(4), M. O'Donovan(5), E.
Domenici(6,7), M. Rietschel(8), W. Maier(9), O. Mors(10), J.
Hauser(11)
1. King's College London 2. University of Geneva 3. Pfizer, Groton
4. 4University of Bristol 5. University of Cardiff 6. Glaxo Smith
Kline 7. Roche 8. Central Institute of Mental Health 9. University of
Bonn 10. Aarhus University Hospital 11. Poznan University of
Medical Sciences
*rudolf.uher@kcl.ac.uk
Introduction: Genomic determinants of response to antidepressants
can be translated into clinical care through personalized treatment
choice and inform development of new therapeutics to target resistant
cases. However, identification of genomic variants that predict
individual differences in treatment response has been hindered by
several obstacles including a complex longitudinal phenotype,
difficulty in obtaining large high-quality clinical samples, nonspecific
‘placebo’ response and limits inherent in the design of
clinical trials.
Methodology: NEWMEDS, a collaboration of academic and
industrial partners (http://www.newmeds-europe.com/), assembled a
combined sample of over 2000 cases of moderate to severe
depression with prospective outcome data on up to 12 weeks
treatment with either a serotonin reuptake inhibiting antidepressant
(SRI) or a norepinephrine reuptake-inhibiting (NRI) antidepressant.
The genome-wide analyses were powered to detect a clinically
significant effect for polymorphisms with a minor allele frequency of
10% or more. Four primary genome-wide analyses tested the
hypotheses that common genetic variant exist that have a clinically
significant effects on (1) response to any antidepressant, (2) response
to SRI, (3) response to NRI, or (4) that differentially predict response
to SRI and NRI antidepressants. These primary analyses were
followed up with a variety of secondary approaches.
Results: No association reached genome-wide significance (p

TRANSCRIPTOMIC AND EPIGENETIC CORRELATES OF
ANTIDEPRESSANT RESPONSE
F. Mamdani, J. Lopez, M. Berlim, A. Labbe, G. Turecki*
McGill University
*gustavo.turecki@mcgill.ca
Introduction: There is significant variability in antidepressant
treatment outcome, with approximately 30-40% of patients with
major depressive disorder (MDD) not presenting with adequate
response even following several trials. To identify potential gene
expression and epigenetic biomarkers of response we investigated
peripheral gene expression patterns of response to antidepressant
treatment in MDD.
Methodology: We used Affymetrix HG-U133 Plus2 microarrays in
blood samples from untreated individuals with MDD (N = 63)
ascertained at a community outpatient clinic, pre- and post eightweek
treatment with citalopram and used a regression model to assess
the impact of gene expression differences on antidepressant response.
We carried out technical validation of significant probesets by qRT-
PCR and conducted CNS follow-up of the most significant result in
post-mortem brain samples from MDD and control individuals.
Epigenetic investigation of differentially expressed genes was carried
out.
Results: A total of 32 probesests were differentially expressed
according to response to citalopram treatment following FDR
correction. Interferon Regulatory Factor 7 (IRF7) was the most
significant differentially expressed gene and its expression was
upregulated by citalopram treatment in individuals who responded to
treatment. Consistent results were found in postmortem brain tissue
of MDD subjects and epigenetic mechanisms seem to play a relevant
role.
Conclusions: These findings point to IRF7 as a gene of interest in
studies investigating genomic factors associated with antidepressant
response.
8
AN APPROACH TO EMPLOY ANIMAL STUDIES TO
INFORM HUMAN PHARMACOGENETICS
M. Popoli*
Center of Neuropharmacology-Department of Pharmacological
Sciences, University of Milano
*maurizio.popoli@unimi.it
Introduction: Research in rodent models may contribute to identification of
genomic determinants of response to drugs. This objective can be pursued by
employing different rodent models, with the use of stress paradigms or
transgenics reproducing genetic variants linked to neuropsychiatric disorders,
and treating the animals with different drugs. The kinds of techniques that can
be used range from transcriptomics and proteomics to the more recent
epigenetic methods. Aim of this presentation will be to draw from different
animal studies a number of converging, validated genes and pathways that
may inform human pharmacogenetic studies.
Methodology: Select results will be presented from a number of studies
including: (1) Transcriptomics of the Flinders Sensitive Line (FSL) genetic
model of depression (2) Synaptoproteomics of FSL subjected to early-life
stress (gene x environment model) (3) Synaptoproteomics of the Learned
Helplessness (LH) model (4) Epigenetic analysis of transgenic mice carrying
the BDNF Val66Met human mutation (5) Analysis of microRNAs (miRs)
involved in the action of antidepressants.The studies on FSL and LH models
of depression have been carried out within the GENDEP Consortium, funded
from EU in the FP6 Program. Both FSL and LH are validated and previously
characterized animal models of depression. Some of these studies have been
published [1-3].Epigenetic mechanisms, self-perpetuating changes in
chromatin that alter gene expression, regulate CNS physiology and have a role
in both neuropsychiatric pathophysiology and drug action. The BDNF
Val66Met transgenic mouse is the first animal model that fully recapitulates
the established phenotypic effects of a common human polymorphism
expressed in brain, including reduced hippocampal size and dendritic
complexity, deficit in extinction learning and NMDA receptor-dependent
synaptic plasticity. The data that will be presented come from the first
epigenetic analysis of BDNFMet mice and may contribute to explain some of
the phenotypic features of Met allele carriers.miRs have recently emerged as
key regulators of complex temporal and spatial patterns of gene/protein
expression changes and, thereby, neuroplasticity. The present study is the first
analysis of the effects of different chronic antidepressant treatments on miRs
and respective target genes.
Results: A common result of the studies on FSL and LH models was the
finding that energy metabolism and cellular remodeling pathways are
involved in both the depressive-like phenotype and in the response to
antidepressants. A number of interesting biomarkers was regulated in opposite
ways by stress and antidepressants in both models. Results with the BDNF
Val66Met mice have been obtained both from candidate gene studies and
from a genome-wide ChIP-Seq study. Bioinformatic analysis of genes with
epigenetic changes in their promoters revealed the involvement of the KEGG
“Neuroactive ligand-receptor”, “MAPK signaling” and “Regulation of actin
cytoskeleton” pathways. In addition, consistent changes in epigenetic tags and
in expression have been found in select splice variants of BDNF transcripts.
Conclusions: The results obtained in the different rodent studies summarized
above allowed to select a number of genes and pathways that were involved in
pathophysiology as well as in response to drug treatments. Converging results
from different studies and models will be implemented to inform human
pharmacogenetic research.
References
1. Blaveri et al. (2010) PloS ONE5(9):e12596.
2. Carboni et al. (2010) Progr Neuropsychopharmacol & Biol
Psychiatry16:1037-48.
3. Mallei et al. (2010) Neuropharmacology2010 Dec 31. [Epub ahead of
print].

IMAGING INTERMEDIATE PHENOTYPES OF
DEPRESSION INCLUDING RESPONSE TO THERAPY:
OVERVIEW AND CONCEPTUAL LINKS TO GENETICS
P. Sämann*(1), D. Höhn(1), M. Czisch(1), M. Kohli(1), S. Lucae(1),
B. Inkster(2,3), P. Matthews(2,3), L. Dixson(2), T. Kam-Thong(1),
B. Müller-Myhsok(1), E. Binder(1), F. Holsboer(1)
1. Max Planck Institute of Psychiatry 2. GlaxoSmithKline Clinical
Imaging Centre, HammersmithHospital 3. Department of Clinical
Neuroscience, Imperial College
*saemann@mpipsykl.mpg.de
Introduction: Imaging genomics builds associations between genetic
variability and variability of neuroimaging measures. In the context
of depressive disorders, imaging genomics may pursue different
goals: (i) imaging studies performed on known genetic variants
associated with depression phenotypes to explore their functional
impact, (ii) validation of newly detected genetic variants by
projection onto an intermediate phenotype, (iii) search for genetic
underpinnings of depression phenotypes by the use of intermediate
phenotypes. While (i) is the most commonly used approach, (ii) and
(iii) are now also increasingly employed with(iii) representing a
particularly promising application of the original endophenotype
concept.
Methodology: An example of a candidate gene approach (i) is given
from recent analyses on Methyl CpG binding protein (MECP2)
variants directed to brain morphology and 1H-MR-spectroscopy (1H-
MRS). MRI data for analysis (i) and (iii) were acquired at the Max
Planck Institute of Psychiatry, Munich, comprising 525 structural
MRI scans (225 healthy adults, 300 patients with single episode or
recurrent major depression), including a subgroup of 176 subjects
with 1H-MRS. Concept (ii) is employed within the convergent
approach framework that aims at proving evidence for true causal
gene-phenotype relationship by integrating different functional
assays. As an example, results from a genetic variant revealed by a
whole genome case/control study are picked up. For (iii), literature
based imaging based endophenotypes of response to antidepressant
treatment are given. Further, a whole genome association study
focussing on hippocampal structural measures is presented.
Results: Ad (i): The analysis of MECP2-rs2239464 revealed
genotype X group interactions on cortex volume of lower medial
prefrontal cortex (mPFC) areas including the subgenual area. A
similar interaction was also found with respect to mPFC glutamate/
glutamine levels, pointing out an interaction between MECP2 and
recurrent depression potentially related to epigenetic mechanisms. Ad
(ii): A newly detected genetical variant in a neuronal transporter gene
conveying risk for depression was found associated with reduced
hippocampal integrity and glutamate levels in healthy risk allele
carriers, and with altered hippocampal grey matter volumes in risk
allele carrying patients. Ad (iii): A whole genome association study
focussing on whole genome wide SNP X SNP interaction effects on
hippocampal structural markers is described.
Conclusions: By exemplary studies it is demonstrated that the
intermediate phenotype idea is a flexible and powerful concept to
study the influence of genetic variants that convey risk to develop
depression or that are associated with treatment response. Imaging
studies on candidate genes have been successfully employed to build
new hypotheses on how these variants translate into behavioral
patterns. Strict adherence to the endophenotype concept is needed
when newly detected phenotype-genotype associations are validated
by neuroimaging. Last, gene search studies into which imaging based
phenotypes are entered are a rather new approach in depression
research.
9

PLENARY
ABSTRACTS
10

PLENARY 1: THE ROLE IN DISEASE OF SYNAPSE
PROTEIN COMPLEXES AND COMPLEXITY
S. Grant*
The Wellcome Trust Sanger Institute
*sg3@sanger.ac.uk
Recent work combining synapse proteomics and human genetics
shows multiprotein complexes in the postsynaptic proteome are
disrupted by mutations in over 200 genes causing over 130 brain
diseases (Bayes et al, 2011). A subset of these proteins assemble into
multiprotein complexes known as the MAGUK Associated Signaling
Complex (MASC) that is involved in over 50 diseases including
schizophrenia, bipolar disease and autism. A large scale mouse
genetic screen identifies sets of MASC proteins that mediate adaptive
behaviours and higher cognitive functions. MASC is a signaling
complex linking neurotransmitter receptors to intracellular pathways
and thereby mediates behavioural responses. Comparative genomic,
proteomic and behavioural genetic studies show a strong
conservation of function in these complexes in mammals and provide
new approaches to animal models of human disease.
11
PLENARY 2: ASSOCIATION METHODS FOR RARE
ALLELES
S. Leal*
Baylor College of Medicine
*sleal@bcm.edu
There is currently great interest in detecting rare variant associations
using next generation sequence data. A large number of association
methods which aggregate variants across a region e.g. a gene have
been developed specifically to analyze rare variant data. It is not clear
which existing method is the most powerful and should be applied to
test for associations using exome/genome sequence data. It is difficult
to compare rare variant association methods because there is no
standard to generate data and often the comparisons are biased. To
fairly compare rare variant association methods it is necessary to
generate data using realistic population demographic and phenotype
models. The power was compared for a variety of methods to detect
associations for qualitative and quantitative traits. Power was
evaluated for case-control, extreme quantitative trait sampling and
population based study designs. For each method, power was
determined for scenarios which included 1. analysis of a. only rare
variants & b. rare (

PLENARY 3: NIMH FUNDING PRIORITIES FOR GENETICS
T. Insel*, T. Lehner*
National Institute of Mental Health
*tinsel@mail.nih.gov, *tlehner@mail.nih.gov
In spite of a flattening of the NIH budget, the NIMH has continued to
invest in and grow the genetics portfolio relevant to mental
disorders. The conceptual and technological advances of
contemporary genomics have presented unprecedented opportunities
to map the biological basis of risk for mental disorders. The
American Recovery and Reinvestment Act of 2009 presented an
unexpected opportunity for NIMH to make additional large
investments in psychiatric genetics and to generate additional
resources for the community as we move from genotyping to
sequencing to multiplexed approaches with epigenomics,
transcriptomics, proteomics, and imaging. The advent of iPS cells
promises a powerful new approach for moving from genetic variation
to a deeper understanding of the mechanisms by which
neurodevelopmental disorders, such as schizophrenia and autism,
may develop. The speakers will discuss funding trends and priorities
in genetics for NIMH, including the large investments by NIMH into
genomic resources for the global investigator community. The level
of NIH funding in 2012 remains uncertain, but most predict cuts
below the President's recommended budget. The potential impact of
budgetary constraints on the field going into the future will be
discussed.
12
PLENARY 4: MODELING HUMAN GENETIC DISEASE IN
THE LABORATORY
N. Katsanis*
Duke University Medical Center
*katsanis@cellbio.duke.edu
Defects of the primary cilium and its anchoring structure, the basal
body, cause a number of human genetic disorders, collectively
termed ciliopathies, since they are characterized by an overlapping
range of phenotypes that include retinal degeneration, polydactyly,
renal and hepatic fibrosis, obesity and a complex range of cognitive
and neurodevelopmental defects. Recent data have also shown that
some ciliopathies overlap not only phenotypically, but also
genetically by contributing epistatic alleles that can modulate the
phenotypic expressivity and penetrance. As such, the primary cilium
and its associated signaling represent a useful model to understand
the mechanism of total mutational load in a biological system.
Towards that end, we have initiated systematic sequencing and
functional evaluation of mutations of ciliary genes in a range of
ciliopathy phenotypes and, using a large allelic series, have
constructed models of epistasis in oligogenic disorders that suggest
an intricate interaction between rare and common alleles to modulate
penetrance and expressivity. Such studies will ultimately empower
the predictive nature of the genotype and inform clinical management
and treatment. Importantly, coupling deep medical resequencing with
systematic in vivo and in vitro functional testing offers significantly
improved resolution and increased appreciation of the complexity and
architecture of genetic disease.

PLENARY 5: GENETIC DISSECTION OF COMPLEX
TRAITS
A. Chakravarti*
Johns Hopkins University
*aravinda@jhmi.edu
Introduction: The genetic bases for complex diseases and
quantitative traits have remained an open problem in genetics for
close to a century.
Although much progress have been made in our understanding, from
theoretical models and in model systems, the natural variation that
contributes to these traits remain elusive. I will discuss our efforts at
understanding two medically relevant human neuronal disorders,
Hirschsprung disease and autism, and how progress in these disorders
have taught us the relevant lessons as to why traits and diseases are
complex.
13
PLENARY 7: GENETIC INFLUENCES ON IMPULSIVITY
D. Goldman*
National Institute of Health
*davidgoldman@mail.nih.gov
Impulsivity, describing action without foresight, is a precursor and
mediating factor in several psychiatric diseases including addictions
and personality disorders. Impulsivity is a modifier of other
psychiatric diseases, for example contributing to suicidality.
Functional alleles mediate the heritability of impulsivity and
disorders with which it is associated. Alleles mediating risk for
psychiatric disease are both common and uncommon, and of different
effect sizes, however their actions appear to be stronger on
intermediate phenotypes, including heritable endophenotypes. For
example, a functional variant of Neuropeptide Y exerts strong effects
on molecules, and intermediate effects on brain responses, but
weaker effects on anxiety (Zhou et al, Nature, 2008). Via genome
wide association, CHRNA5 Asp398Asn was identified as a risk factor
in nicotine addiction. Via a study of functional connectivity, we
found that the risk allele, Asn398, exerts a much larger effect (11% of
the variance) on the connectivity of multiple brain circuits (Hong et
al, PNAS, 2010), potentially clarifying how Asn398 could modify
vulnerability. The circuits weakened by Asn398 include a dorsal
anterior cingulate/ventral striatal circuit that predicts nicotine craving.
To find rare and uncommon alleles contributing to impulsivity we
used next generation sequencing in severely impulsive individuals
from a founder population, Finland. Echoing the discovery of Han
Brunner of an MAOA stop codon that led to impulsivity in one Dutch
family, we identified a stop codon, Q20*in the serotonin HTR2B
receptor. *20 led to variable nonsense-mediated decay of the HTR2B
mRNA and complete blockade of receptor expression. *20 was
necessary for severe impulsivity displayed by some individuals in our
sample of violent offenders, but not alone sufficient. Other important
factors were male sex and inebriation with alcohol. *20 was
associated with disorders marked by impulsivity and co-segregated in
families. It did not lead to global cognitive deficits. *20 is apparently
population-specific but common in Finns, with an allele frequency
>1%, echoing findings made for various medical genetic diseases,
where genetic heterogeneity is dramatically reduced in this
population. Mice knocked out for htr2b are impulsive and novelty
seeking. Genomic approaches, tied to deep phenotyping and study of
appropriate human populations and animal models, are identifying
rare and common alleles that underly heritability of traits such as
impulsivity, and offer an avenue to the identification of genes whose
rare and uncommon alleles modulate behavior.

SYMPOSIA
ABSTRACTS
14

SYMPOSIUM 1: NEW INSIGHTS FROM CNV STUDIES IN
SCHIZOPHRENIA
S1.1 DE NOVO CNVS IN SCHIZOPHRENIA ARE
ENRICHED FOR PATHOGENIC EVENTS AND DIFFER
FROM INHERITED CNVS
G. Kirov*(1), M. O'Donovan(1), D. Ivanov(1), M. Ikeda(1), E.
Rees(2), D. Ruderfer(3,4,5), J. Moran(5), K. Chambert(5), P.
Sklar(5), S. Purcell(5), D. Grozeva(1), P. Olason(6), Y. Böttcher(6),
H. Stefansson(6), K. Stefansson(6), M. Owen(1)
1. Cardiff University 2. Fujita Health University 3. Massachusetts
General Hospital and Harvard Medical School 4. Massachusetts
General Hospital 5. Broad Institute 6. deCODE genetics
*kirov@cardiff.ac.uk
Introduction: We hypothesized that CNVs occurring de novo as new
mutations in individuals affected with schizophrenia are particularly
likely to be relevant to the pathogenesis of this disorder.
Methodology: Samples were genotyped with Affymetrix 6.0 arrays
and filtered with the z-score method.
Results: Using 638 informative families, we found 34 rare de novo
CNVs in 662 schizophrenia probands, a rate of 5.1%. This is over 2fold
higher compared with a rate of 2.2% in 2623 Icelandic
individuals without a history of neurodevelopmental disorders.
Several of the de novo CNVs found in schizophrenia are in loci
already implicated in disease pathogenesis: 3q29, 15q11.2, 15q13.3
and 16p11.2. This supports the conclusion that they are enriched for
pathogenic loci. The median size of the de novo CNVs was 320.8kb.
This makes them much larger than the 1300 rare CNVs found in 605
unaffected controls from the Bulgarian population, genotyped and
called using the same methods (median size = 69.4kb, P=1.6x10 -7 ).
However the de novo CNVs found in schizophrenia were very similar
in size to de novo CNVs identified in unaffected controls from the
Icelandic population.
Conclusions: We postulate that de novo CNVs are more pathogenic
in general, as they have yet to subjected to natural selection. This
makes them different in size and other properties to CNVs found in
the general population.
15
S1.2 DE NOVO COPY NUMBER VARIANTS CONFER RISK
FOR EARLY ONSET BIPOLAR DISORDER
AND SCHIZOPHRENIA
D. Malhotra*(1), S. Mccarthy(2), K. burdick(3), A. malhotra(4), E.
leibenluft(5), J. potash(6), F. mcmahon(7), T. schulze(8), S.
cichon(9), M. reitschel(10), J. kelsoe(1), E. gershon(12), D. levy(13),
A. corvin(14), M. karayiorgou(15), J. sebat(1)
1. Department of Psychiatry,University of California, San Diego 2.
Stanley Center for Cognitive Genomics, Cold Spring Harbor
Laboratory 3. Zucker Hillside hospital, NorthShore Long Island
Jewish health system 4. Zucker Hillside hospital, NorthShore Long
Island Jewish health system 5. Section on Bipolar Spectrum
Disorders, Mood and Anxiety Disorders Program, NIMH Building
15K -MSC 2670 6. The Johns Hopkins Hospital, John Hopkins
University, 600 North Wolfe Street 7. Genetic Basis of Mood and
Anxiety Disorders, National Institute of Mental Health, NIH,
Convent Drive MSC 3719 8. Department of Psychiatry and
Psychotherapy, University of Gottingen 9. Department of Genomics,
Life and Brain Center, University of Bonn 10. Central Institute of
Mental Health, Square J5, 68159 11. Department of
Psychiatry,University of California, San Diego 12. Department of
Psychiatry and Behavioral Neuroscience, University of Chicago 13.
McLean Hospital 14. Neuropsychiatric Genetics Research Group,
Institute of Molecular Medicine and Department of Psychiatry,
Trinity College 15. Department of Psychiatry, Columbia University
16. Department of Psychiatry,University of California, San Diego
*dmalhotra@ucsd.edu
Introduction: Family-based studies of copy number variation (CNV)
have demonstrated that rare spontaneous mutations play a role in
neuropsychiatric disorders including autism (ASD) and schizophrenia
(SZ). However, the relevance of such mutations to bipolar disorder
(BD) has not been established. We tested the hypothesis that de novo
CNVs are enriched in BD subjects with early age-at-onset (AAO≤18)
and we sought to confirm the strong association of de novo CNVs in
SZ.
Methodology: Using a microarray consisting of 2.1 million probes,
we screened for de novo CNVs ≥10 kb in size in blood derived DNAs
from 788 subject-mother-father trios. Diagnoses of subjects included
BD (N=185), SZ (N=177) and healthy controls (N=426). CNVs were
subsequently validated by a custom tiling-resolution array
comparative genomic hybridization (CGH) platform.
Results: A total of 23 de novo CNVs were detected. Mutations were
detected in 0.9% of controls and at significantly increased rates in BD
(4.3%, P=0.009) and SZ (4.5%, P=0.007). In BD, the observed effect
was mainly in probands with AAO≤18 (5.6%, P=0.006) and not in
late onset BD (2.6%, P=0.22), as hypothesized, while in SZ, we did
not observe a similar trend. De novo CNVs had a median size of 112
kb and contained a median of 2 genes.
Conclusions: Our findings provide evidence that de novo structural
mutations are associated with BD, particularly in cases with an early
disease onset. Genes identified in this study may help to elucidate the
neurobiological basis of mood disorders and other psychiatric
disorders.

S1.3 DE NOVO CNV ANALYSIS IMPLICATES SPECIFIC
GENETIC ABNORMALITIES IN THE PATHOGENESIS OF
SCHIZOPHRENIA
M. Owen*(1), A. Pocklington(1), P. Holmans(1), D. Ivanov(1), S.
Grant(2), P. Sklar(3,4,5), S. Purcell(3,4,5), D. Ruderfer(3,4,5), J.
Moran(5), K. Chambert(5), L. van de Lagemaat(2), À. Bayés(2), E.
Fernandez(2), N. Komiyama(2), G. Kirov(1), M. O'Donovan(1)
1. Cardiff University 2. Wellcome Trust Sanger Institute 3.
Massachusetts General Hospital and Harvard Medical School 4.
Center for Human Genetics Research 5. Broad Institute
*owenmj@cf.ac.uk
Introduction: Rare, recurrent copy number variants (CNVs) are
known to substantially increase susceptibility to schizophrenia. We
postulated that de novo CNVs are particularly likely to be relevant to
pathogenesis.
Methodology: We used Affymetrix 6.0 arrays to genotype 662
patients suffering with schziophrenia and all their parents. Data were
filtered for the presence of LCRs, frequency >1%, >15kb size, and
with the median z-score method. Potential de novo CNVs were
validated with Agilent custom arrays.
Results: We found that de novo CNVsoccurred in 5.1% of 662
schizophrenia probands and were enriched for known and novel
pathogenic loci. The occurrence of multiple de novo CNVs
implicated EHMT1 as well as DLG2, whose orthog is directly
regulated in Drosophila by the orthlog of EHMT1, and other
members of the membrane-associated guanylate kinase (MAGUK)
family of proteins. Genes within the de novo CNVs were
significantly enriched for membership of the postsynaptic density
(PSD p=1.72 x 10 -5 ) largely as a consequence of enrichment for
membership of N-Methyl-D-Aspartate receptor (NMDAR
p=1.30x10 -5 ) and neuronal activity-regulated cytoskeleton-associated
protein complexes (ARC p=1.07x10 -6 ).
Conclusions: This work provides strong evidence that specific
synaptic complexes implicated in cognitive function and neuronal
plasticity are highly enriched for rare mutations that contribute to
schizophrenia pathogenesis.
16
S1.4 CNVS BETWEEN SCHIZOPHRENIA AND
NEURODEVELOPMENTAL DISORDERS
D. Rujescu*(1), H. Stefanson(2), A. Ingason(1), S. Steinberg(2), S.
Cichon(3), R. Ophoff(4), E. Sigurdsson(5), S. Tosato(6), A.
Palotie(7), M. Franziska Degenhardt(3), O. Andreassen(8), T.
Werge(9), M. Rietschel(10), D. Collier(11), D. St Clair(12), K.
Stefansson(1)
1. Division of Molecular and Clinical Neurobiology, Department of
Psychiatry, Ludwig-Maximilians-University, Nußbaumstrasse 7,
80336 Munich, Germany 2. deCODE genetics, Sturlugata 8, IS-101,
Reykjavik, Iceland 3. Institute of Human Genetics Department of
Genomics Life & Brain Center University of Bonn Sigmund-Freud-
Strasse 25 D-53105 Bonn, Germany 4. Rudolf Magnus Institute of
Neuroscience and Department of Medical Genetics, University
Medical Center, 3584 CG Utrecht, The Netherlands 5. Department of
Psychiatry, National University Hospital, Hringbraut, IS-101
Reykjavik, Iceland 6. Section of Psychiatry and Clinical Psychology,
University of Verona, Verona, 37134 Verona, Italy 7. Wellcome
Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton,
Cambridge, CB10 1SA, UK 8. Division of Mental Health and
Addiction, Oslo University Hospital & Institute of Clinical Medicine,
University of Oslo, Kirkeveien 166, PO Box 4956 Nydalen, 0424
Oslo, Norway 9. Institute of Biological Psychiatry, Mental Health
Centre Sct. Hans Copenhagen University Hospital, DK-4000
Roskilde, Denmark 10. Department of Genetic Epidemiology in
Psychiatry, Central Institute of Mental Health, University of
Heidelberg, J5, D-68159 Mannheim, Germany 11. Social, Genetic
and Developmental Psychiatry Centre, Institute of Psychiatry, King's
College, London SE5 8AF, UK 12. Department of Mental Health,
University of Aberdeen, Royal Cornhill Hospital, Aberdeen AB25
2ZD, UK
*dan.rujescu@med.uni-muenchen.de
Introduction: A major challenge in medicine is to understand
genetic, molecular and cellular mechanisms underlying mental
disorders including schizophrenia, which involves complex genetic
and environmental determinants. The last few years brought up a
series of studies in schizophrenia which substantially advanced the
knowledge on the genetic causes and had a major impact on the field.
Especially genome-wide studies on Copy Number Variants (CNVs)
raised highest interests. These techniques have shown that a much
higher number of CNVs exists in humans than previously recognized.
Methodology: Interestingly, some of the discovered deletions in
schizophrenia have been shown to associate with a number of
unexpected phenotypes, including minor dysmorphic features,
abnormal EEG, significant expressive language deficits, and a
spectrum of neuropsychiatric impairments that include epilepsy,
ADHD, autism spectrum disorder, and cognitive impairment varying
from moderate to mild learning disability. Thus, CNV carriers need
to be carefully characterised regarding clinical signs and symptoms,
as well as cognitive and behavioural features across diagnostic
boundaries.
Results: In a genome-wide search for CNVs associating with
schizophrenia performed by the SGENE consortium, a population
based sample was used to identify de novo CNVs. Beside these
finding at 1q21.1, 15q11.2 and 15q13.3, further CNV studies were
performed. e.g. CNVs were reported in the NRXN1 gene (2p16.3),
furthermore, 15q11-q13 duplications were detected in a
region overlapping the Prader-Willi/Angelman syndrome or at
16p13.1, which has been implicated in childhood-onset
developmental disorders.
Conclusions: All these studies as well as new results will be
presented and critically discussed.

SYMPOSIUM 2: GENES TO BIOLOGY IN
UNDERSTANDING OF NICOTINE DEPENDENCE
S2.1 SMOKING AND GENETIC RISK VARIATION ACROSS
POPULATIONS OF EUROPEAN, ASIAN, AND AFRICAN
ANCESTRY - A META-ANALYSIS OF CHROMOSOME
15Q25
L. Chen*, L. Bierut, C. Meta-Analysis Group
Department of Psychiatry, Washington University School of
Medicine
*chenli@psychiatry.wustl.edu
Introduction: Recent meta-analyses of genetic data from subjects of
European ancestry show strong evidence for association between
smoking quantity and multiple genetic variants on chromosome
15q25. This study extends the examination of association between
distinct loci in the CHRNA5-CHRNA3-CHRNB4 region and smoking
quantity to populations of Asian and African ancestry to refine
specific reported associations.
Methodology: The analyses of a dichotomized cigarettes smoked per
day (CPD) phenotype in 27 datasets (subjects of European, Asian,
and African American ancestry N=14,786, 6,889, 10,912
respectively, for a total of 32,587 subjects who smoked) were metaanalyzed.
To refine the reported loci associated with heavy smoking,
we examined all available variants in each population.
Results: We demonstrate the association between smoking quantity
and genetic loci in the chromosome 15q25 region across all three
populations and narrow the region of association. The most strongly
associated variant seen consistently across the three populations is
rs16969968 (OR=1.33, 95%C.I.=1.25-1.42, p=1.1x10 -17 ). Another
locus displayed a consistent signal in both European and Asian
ancestry, but not in African American ancestry.
Conclusions: Multiple distinct genetic variants on chromosome
15q25 are associated with smoking quantity across diverse
populations. Further, our results narrow the regions of association.
The observed consistent associations of rs16969968 with heavy
smoking across different populations, combined with its functional
significance, suggest that rs16969968 is most likely a causative
variant in this region. Additional distinct genetic variants may also
be associated with heavy smoking across populations. Using the
cross-population study paradigm provides valuable insights to inform
future biological experiments.
17
S2.2 NICOTINIC RECEPTORS IN THE HABENULO-
INTERPEDUNCULAR TRACT REGULATE NICOTINE
INTAKE
P. Kenny*
Scripps Florida
*pjkenny@scripps.edu
Introduction: Tobacco smoking results in more than 5 million
deaths each year and accounts for almost 90% of all deaths from lung
cancer. Nicotine is the major reinforcing component in tobacco
smoke responsible for addiction. Nicotine acts in the brain through
neuronal nicotinic acetylcholine receptors (nAChRs). Twelve
neuronal nAChR subunits have been identified: nine αsubunits (α2–
α10) and three β subunits (β2–β4). The predominant nAChR subtypes
in brain are those containing α4 and β2 subunits. A major advance in
our understanding of smoking behaviour is the finding that variation
in the α5/α3/β4 nAChR subunit gene cluster located in chromosome
region 15q25 significantly increases risk of tobacco addiction. In
particular, polymorphisms in the α5 subunit gene (CHRNA5), which
result in decreased function of the subunit, increase vulnerability to
tobacco addiction. In addition, polymorphisms in the α3 subunit also
greatly increase vulnerability to tobacco dependence. Here, we
investigated the mechanisms through which α5-containing (denoted
as α5*) nAChRs and a3* nAChRs influence the reinforcing
properties of nicotine. As α5* and a3* nAChRs are densely expressed
in the medial habenula (MHb) and/or interpeduncular nucleus (IPN),
we also assessed the role for these nAChRs in the habenulointerpeduncular
tract in regulating nicotine intake.
Methodology: The reinforcing properties of nicotine were measured
in rats and mice by means of the intravenous nicotine selfadministration
behavior. Nicotine reinforcement was assessed in
wildtype (WT) and α5 nAChR subunit knockout (α5 KO) mice. The
expression of α5 nAChR subunits was “rescued” in discrete brain
regions of the α5 KO mice through lenti-virus-mediated reexpression.
Conversely, α5 or α3 naChR subunits were knocked
down in discrete brain regions in rats by means of lentivirus-mediated
delivery of short-hairpin interfering RNAs against these subunits.
Finally, the effects of nicotine on brain reward systems were
measured using alterations in intracranial self-stimulation (ICSS)
thresholds in rats.
Results: The α5 KO mice self-administered far greater quantities of
nicotine than their WT counterparts, and this effect was most
evidence when high unit doses of nicotine were available. Virusmediated
re-expression of α5 subunits in the habenulointerpeduncular
tract of KO mice, achieved through virus infusions
into MHb, normalized the increased intake detected in KO mice.
Conversely, virus-mediated knockdown of α5 subunits in the
habenulo-interpeduncular tract resulted in greater nicotine intake in
rats. Knockdown of α5 subunits in MHb of rats did not alter the
rewarding effects of nicotine, measured as nicotine-lowered ICSS
thresholds, but abolished the inhibitory effects of higher nicotine
doses on brain reward systems, reflected in nicotine-elevated ICSS
thresholds. Finally, knockdown of α3 subunits in MHb or IPN of rats
also increased their responding for nicotine.
Conclusions: Taken together, these findings demonstrate that α5*
and a3* nAChRs in the habenulo-interpeduncular tract negatively
regulate nicotine self-administration behavior in rats and mice. This
action is related to the fact that these nAChRs regulate the inhibitory
effects of higher nicotine doses on brain reward circuitries. Genetic
variation that results in diminished function of nAChRs containing α5
and/or a3 subunits may therefore increase vulnerability to tobacco
addiction by reducing the aversive effects of nicotine, permitting
greater quantities of tobacco to be consumed.

S2.3 IMPORTANCE OF α4β2α5 AND α6β2β3 * ACHRS IN
POTENTIAL DRUGS FOR NICOTINE DEPENDENCE
J. Lindstrom*, A. Kuryatov
University of Pennsylvania
*jslkk@mail.med.upenn.edu
Introduction: Previous studies showed that α5 398N is a risk variant
for nicotine dependence, lung cancer and certain cognitive defects
and that (α4β2)2α5 AChRs with the risk sequence exhibited reduced
function. α5, α3, and β4 genes are located contiguously in the
genome. (α3β4)2α5 and (α3β2)2α5 are prominent postsynaptic AChR
subtypes in autonomic ganglia and enteric neurons, but are rare in
brain. (α4β2)2α5 AChRs are a significant presynaptic subtype among
brain α4β2 * AChRs. Knock out of α5 in the medial habenula
increases nicotine self-administration. Previous studies showed that
(α6β2)(α4β2)β3 presynaptic AChRs on dopaminergic neurons are the
most sensitive subtype to activation by nicotine. Knock out of either
α4, α6 or β2 subunits in the ventral tegmental area prevents selfadministration
of nicotine. Mixtures of free α6, α4, β2 and β3
subunits do not result in expression of homogenous populations of
functional AChRs of the desired complex subtypes.
Methodology: Human α3 and α4 AChR subtypes containing α5
subunits with either D or N398 were assayed for function
electrophysiologically after expression in Xenopusoocytes. Human
AChR subtypes containing α5 subunits with D398 expressed in
permanently transfected HEK cell lines were assayed for function
using a fluorescent indicator of membrane potential. Functional
human α6β2β3 * AChR subtypes of defined subunit composition and
order were expressed in Xenopusoocytes using concatameric
constructs with (AGS)n linkers between the C-terminal amino acid of
one subunit and the N-terminal amino acid of the next.
Results: The α5 N398 risk variant reduced Ca ++ permeability and
increased desensitization in (α4β2)2α5 but not (α3β4)2α5 or
(α3β2)2α5 AChRs, compared to the α5 D398 variant. Sensitivity to
activation was not altered. The high sensitivity to activation and
desensitization of (α4β2)2α5 AChRs results in a narrow concentration
range in which activation and desensitization curves overlap. This
region centers at 0.2 µM nicotine, a concentration sustained in
smokers. This concentration desensitizes 60% of these AChRs and
permits smoldering activation of the remainder. The low sensitivity to
activation and desensitization of (α3β4)2α5 by nicotine results in
negligible activation or desensitization by 0.2 µM nicotine. α6β2β3 *
AChRs can be expressed as concatamers using 1, 2, 3, or 4 linkers.
Linking the accessory β3 subunit to α6 or α4 is critical to insure
assembly. Concatameric pentamers are sensitive to activation by
nicotine and by putative α4β2 AChR-specific agonists such as
varenicline and sazetidine.
Conclusions: The reduced function of (α4β2)2α5 AChRs with the
risk variant α5 N398 and the increased nicotine consumption
observed when α5 is knocked out suggests that it would be valuable
to develop positive allosteric modulator drugs which could increase
the function of AChRs with α5 subunits. The use of cell lines
expressing (α4β2)2α5 and other subtypes provides methods for
selecting such drugs. The sensitivity of (α6β2)(α4β2)β3 AChRs to
activation by nicotine and smoking cessation drugs such as
varenicline, as well as the observation that knock out of α4, α6, or β2
subunits prevents nicotine self-administration, suggests that
antagonists or negative allosteric modulators specific for α6β2β3 *
AChRs would be useful for smoking cessation. The use of
concatameric α6β2β3 * AChRs provides a method for selecting such
drugs.
18
S2.4 REGULATORY POLYMORPHISMS IN NICOTINE
DEPENDENCE RISK GENES
R. Smith*, W. Sadee
The Ohio State University
*smith.4051@osu.edu
Introduction: Genetic variants within nicotinic receptors have been
shown to modulate an individual’s risk for nicotine dependence.
Among the most reproducible risk factor is a non-synonymous
polymorphism (rs16969968) within the alpha5 nicotinic receptor
subunit gene, CHRNA5. Genetic factors also contribute to CHRNA5
mRNA expression and risk for substance abuse, but the specific
variants responsible for changes in mRNA expression are unclear.
Methodology: To determine the presence of cis-acting functional
genetic variants contributing to CHRNA5 mRNA expression, we
measured allelic expression of CHRNA5 within post-mortem human
prefrontal cortex brain tissue. Using allelic expression as a
phenotype, we scanned the CHRNA5 gene locus for polymorphisms
responsible for imbalanced allelic expression. Polymorphisms
determined to be responsible for allelic expression were genotyped in
our full brain cohort and total CHRNA5 expression was compared
across genotype using quantitative PCR. We then tested these
expression-related variants for clinical association with nicotine
dependence.
Results: We uncovered a functional genetic locus 13.5kb upstream of
CHRNA5 acting as an enhancer of CHRNA5 mRNA
expression. Minor allele carriers for enhancer variants displayed >2fold
differences in allelic expression, while individuals homozygous
for the enhancer minor alleles expressed >4-fold more cortical
CHRNA5 mRNA. Haplotype structure analysis predicts that the
enhancer SNPs rarely occur on the same allele as the previously
implicated non-synonymous variant. Taking into account this
relationship, enhancer region SNPs confer significant risk only when
you control for the presence of the non-synonymous variant in a joint
SNP analysis.
Conclusions: Polymorphisms within a transcriptional enhancer
located 13.5kb upstream of CHRNA5 modulate CHRNA5 mRNA
transcription. These enhancer variants confer risk for nicotine
dependence in a context-dependent manner. Understanding the
biological functions of these clinically relevant genetic variants
revealed a SNP-SNP interaction increasing risk for nicotine
dependence that is otherwise obscured by haplotype structure when
using traditional clinical association methods. These findings aid in
the construction of complex biological or genetic models of nicotine
dependence that mimic human factors. The relevance of the enhancer
CHRNA5 polymorphism in other brain regions and peripheral tissues
(e.g., the lung) needs further study. Moreover, identification of
functional CHRNA5 variants facilitates the analysis of gene-gene
interactions with respect to nicotine and other drug addictions.

S2.5 A META-ANALYSIS OF GENE-ENVIRONMENT
INTERACTIONS OF HEAVY SMOKING WITH THE
CHRNA5-A3-B4 GENE CLUSTER
S. Hartz*(1), S. Short(2), P. Kraft(3), L. Bierut(1)
1. Washington University 2. Brown University 3. Harvard University
*hartzs@wustl.edu
Introduction: Recent studies have shown an association between
cigarettes per day (CPD) and a nonsynonymous SNP in CHRNA5,
rs16969968. There is conflicting evidence regarding whether age of
onset of regular smoking, a strong predictor of nicotine dependence,
modifies this association.
Methodology: We conducted a large meta-analysis to determine
whether the association between rs16969968 and CPD is modified by
age of onset of regular smoking. Other variables related to both CPD
and age of onset, including decade of birth, educational attainment,
and gender, were also included in analysis.
Results: The association between rs16969968 and CPD is higher
among early-onset smokers (age of onset of regular use ≤ 16)
compared to later-onset smokers.
Conclusions: The increased association between CPD and
rs16969968 that we found among early-onset smokers supports the
epidemiological observation of an increased rate of nicotine
dependence among early-onset smokers. This gives further credence
to public health interventions targeting adolescent smoking.
19
SYMPOSIUM 3: EXPLORING THE MECHANISMS
UNDERLYING GENOME-WIDE SIGNIFICANT
ASSOCIATIONS WITH PSYCHOSIS
S3.1
GENOME-WIDE SIGNIFICANT RISK VARIANTS FOR
PSYCHOSIS AND NEURAL INTERMEDIATE PHENOTYPES
A. Meyer-Lindenberg*
Central Institute of Mental Health
*a.meyer-lindenberg@zi-mannheim.de
Introduction: While GWAS will probably not provide all answers
about the genetics of schizophrenia, any common variant that does
survive the extreme amount of statistical thresholding that this
method requires certainly merits study using intermediate imaging
phenotypes. Of those variants, the one with the strongest support is
zinc finger protein 804A (ZNF804A) encoding a zinc-finger protein
of unknown, but possibly regulatory function. Like many candidate
gene variants, ZNF804A is pleiotropic on the level of psychiatric
diagnoses, also being associated with bipolar disorder.
Methodology: We use an imaging genetics approach in a sample of
n=110 Germans of German descent genotyped for ZNF804A risk
SNPs and studied using functional neuroimaging,
Results: In functional neuroimaging with an n-back working memory
probe, healthy carriers of risk genotypes exhibit no changes in
regional activity. However, they did exhibit pronounced gene dosagedependent
alterations in functional connectivity, which was decreased
from DLPFC across hemispheres and increased with hippocampus,
similar to findings in patients. These connectivity abnormalities were
specific to working memory. Subsequent workshowed an inability to
downregulate key parts of the mentalizing system in conjunction with
impaired connectivity of this system to DLPFC, suggesting possible
downstream functional activation effects of impaired prefrontal
connectivity that mirror findings in patients. Interestingly,
abnormally increased coupling of amygdala was also observed, a
phenotype unlikely to be related to heritable risk for schizophrenia
and therefore possibly related to risk for bipolar disorder, where
similar findings in patients have been described.
Conclusions: Neural intermediate phenotypes related to risk for
schizophrenia and bipolar disorder through Z NF804A genetic risk
variants can be defined and map onto systems previously implicated
in patients.

S3.2 COGNITIVE & IMAGING CORRELATES OF
GENOME-WIDE SIGNIFICANT RISK VARIANTS FOR
SCHIZOPHRENIA
G. Donohoe, E. Rose, D. Morris, A. Hargreaves, M. Gill, A. Corvin
Neuropsychiatric genetics research group, Department of psychiatry,
Trinity College Institute of Neuroscience and Institute of Molecular
Medicine, Trinity College Dublin
Introduction: Genome wide association studies have resulted in the
identification of a number of novel genetic loci for schizophrenia and
related disorders. Understanding the functional impact of these
variants on brain structure and function is crucial to understand their
role in disease pathology.
Methodology: We profile the neuropsychological,
electrophysiological, and neuro-imaging characteristics of a number
of these variants, including ZNF804A.
Results: Specifically, we will use this data to suggest that while the
risk associated with some genetics variants is being mediated by an
influence on these intermediate phenotypes, other risk variants
delineate illness subtypes in which cognitive deficits are a less
prominent feature.
Conclusions: The implications of these distinctions for the
intermediate phenotypes approach will be discussed.
20
S3.3 FUNCTIONAL ANALYSIS OF THE ZNF804A AND TCF4
SCHIZOPHRENIA SUSCEPTIBILITY GENES
D. Blake, C. Tinsley*
Cardiff University
*tinsleycl@cardiff.ac.uk
Introduction: Recent genome-wide association (GWA) studies have
led to the discovery of several new risk alleles for schizophrenia. For
example, intragenic SNPs in the ZNF804A (2q32.1) and TCF4
(18q21.1) genes are associated with a moderate increase in
schizophrenia risk. Whilst TCF4 is a relatively well-characterised
transcription factor little is known about the biological function of
ZNF804A. The presence of a C2H2 class of zinc finger at the Nterminus
of the protein has led to the speculation that ZNF804A may
be involved in transcription. The aim of this study was to determine
the function of ZNF804A and to identify other genes whose
expression may be regulated by ZNF804A and TCF4.
Methodology: Exon array, interaction trap, chromatin
immunoprecipitation, mass spectrometry.
Results: Complementary strategies have been used to define the
interactomes of ZNF804A and TCF4. We have generated a network
of protein:protein interactions around the ZNF804A and TCF4 nodes
that implicate both proteins as regulators of gene expression. Several
of these interactors include genes that are either transcriptional
activators or co-activators and epigenetic modulators of gene
expression. We have also created cell lines that inducibly overexpress
ZNF804A and TCF4 or where each of the two genes has
been knocked-down. These experiments have shown that bidirectional
changes in the levels of ZNF804A are associated with
altered gene expression defining an initial set of target genes in
human cells. Finally, we have independently validated a number of
physiological targets for TCF4 using luciferase assays and chromatin
immunoprecipitation. Similar experiments with ZNF804A are
ongoing.
Conclusions: Our data show that ZNF804A and TCF4 regulate the
expression of a subset of genes in human cells. The relevance of
these targets to the biology of schizophrenia and allied
neuropsychiatric disorders is currently being determined.

S3.4 MOLECULAR AND CELLULAR MECHANISMS
UNDERLYING GENOME-WIDE SIGNIFICANT
ASSOCIATION BETWEEN ZNF804A AND PSYCHOSIS
M. Hill*, F. Buonocore, A. Jeffries, R. Dobson, J. Price, N. Bray
Institute of Psychiatry, King's College London
*matthew.hill@kcl.ac.uk
Introduction: The first genome-wide significant finding for the
broad phenotype of psychosis (encompassing both schizophrenia and
bipolar disorder) was with SNP rs1344706 within the ZNF804A gene.
Re-sequencing and detailed association analyses have not uncovered
a variant at this locus that is more strongly associated. However, the
molecular and cellular mechanisms by which it impacts on risk for
psychosis are unknown. To address the fundamental mechanisms
underlying ZNF804A association with psychosis, we 1) performed
electrophoretic mobility shift assays (EMSA) to assess potential
allelic differences in the capacity of rs1344706 to bind nuclear
proteins, 2) measured allelic expression of ZNF804A in foetal and
adult human brain and 3) manipulated the expression of ZNF804A in
human neural cells to determine its impact on the cellular
transcriptome.
Methodology: DNA-protein interactions were investigated by EMSA
using extracts from three human neural cell lines and subsequent
incubation with allele specific probes. Relative allelic expression of
ZNF804A was determined in 12 foetal brain samples and across
multiple brain regions in 13 adult subjects. For 3 brain regions
additional subjects were also investigated. Statistically significant
departure from the expected 1:1 allelic ratio of gene expression was
assessed by Mann-Whitney tests. RNA interference using two
separate small interfering RNAs (siRNA) was used to manipulate
ZNF804A expression in a human neural progenitor cell line. The
effects of ZNF804A knockdown on the cellular transcriptome were
compared to a control siRNA by gene expression microarray (n=4 for
each of the 3 conditions). Gene Ontology analysis was performed on
all nominally significant differentially expressed transcripts that were
shared by the two ZNF804A siRNA. High confidence single
transcript differences were determined by Significance Analysis of
Microarrays (SAM) at a false discovery rate of

S4.2 INTEGRATING RNA-SEQ AND GENOME-WIDE
ASSOCIATION TO IDENTIFY RISK GENES FOR
SCHIZOPHRENIA
X. Chen*(1), Y. Zhang(2), J. Chen(1), J. Xu(2), F. Xu(2), Z.
Peng(2), T. Guennel(3), M. Reimers(3), S. Bacanu(1), J. Sun(4), Z.
Zhao(4), K. Kendler(1)
1. Virginia Commonwealth University 2. Beijing Genomic Institute
3. Virginia Commonwealth University 4. Vanderbilt University
*xchen@vcu.edu
Introduction: Genome-wide association studies have identified
several promising candidate genes for schizophrenia, many more risk
genes remain to be discovered. Due to the small effects of these
candidate genes, GWA alone is not effective to identify them. In the
last few years, the progress of DNA sequencing technologies has
made it practical to sequence the entire transcriptome for a reasonable
number of subjects. Both GWA and RNA-seq are systematic
approaches to study the entire genome. Integration of RNA-seq data
with GWA may increase the power of genetic association studies and
improve selection of top candidates.
Methodology: We conducted mRNA sequencing for 82 post-mortem
brain samples (Brodmann area 24) from Stanley Medical Research
Institute, and performed differential expression analyses between
patients of schizophrenia and bipolar disorder and healthy controls.
We also identified SNPs influencing gene expression (eQTL
analyses) in this and other datasets. These data were integrated with
GWA data from the Molecular Genetics of Schizophrenia sample to
identify promising candidates for further studies.
Results: In the RNA-seq expression analyses, we found that
substantially more genes (FDR q ≤ 0.05, N = 608) are differentially
expressed between schizophrenic subjects and healthy controls than
that observed in microarray studies using the same subjects. We also
found that the differential expression of many genes in schizophrenia
patients relative to controls is correlated with the expression changes
of bipolar disorder patients, suggesting a shared liability between the
two disorders. In eQTL analyses of the SPATA7-PTPN21-EML5
locus, one of the top ranked candidate genes from gene-based GWA
analyses of the MGS dataset, SNPs influencing the expression of
these genes are found to be associated with schizophrenia in a metaanalysis
of several independent samples, supporting the idea that
integration of expression data with GWA can improve identification
of candidate genes with small effects.
Conclusions: Expression profiling by RNA-seq is a powerful
approach to identify differentially expressed genes between diseased
and control subjects. Our expression data provided empirical
evidence that schizophrenia and bipolar disorder may share broad
liability. Integration of eQTL and GWA analyses can improve the
power to detect candidate genes with modest effect sizes.
22
S4.3 BRAIN EQTLS AND FUNCTION-BASED GWAS OF
BIPOLAR DISORDER IDENTIFIED NOVEL DISEASE RISK
GENES
N. Cox*(1), E. Gamazon(1), J. Badner(2), L. Cheng(2), F. Pibiri(2),
C. Zhang(2), C. Chen(2), K. Grennan(2), E. Gershon(2), D.
Nicolae(1), B. Consortium(1,2), C. Liu(2)
1. Section of Genetic Medicine University of Chicago 2. Dept. of
Psychiatry and Behavioral Medicine University of Chicago
*ncox@bsd.uchicago.edu
Introduction: Genome-wide association studies (GWAS) with
psychiatric diseases have yielded limited findings, including a few
genome-wide significant associated genes, one polygenic model, and
a few rare copy number variations. Functional annotation of SNPs
may be able to assist the re-evaluation of the genome-wide
association results to recover some lost heritability. One major
function of SNPs is to affect gene expression.
Methodology: We used the genome-wide association study to map
quantitative trait loci of gene expression in human brain. Extensive
statistical analyses take into account covariates (such as brain pH)
and batch effects in the microarray data. Functional SNPs are then
used to perform function-based GWAS analysis to identify novel
disease susceptibility genes of bipolar disorder.
Results: We have identified thousands of SNPs that are associated
with gene expression levels, including different splicing isoforms in
two brain regions. We are applying these data into the re-evaluation
of existing genome-wide association studies of bipolar disorder and
schizophrenia, and have identified novel genes that are associated
with disease but have been missed in previous gene hunting. Three
genes showed genome-wide significant associations (p < 1E-6) in one
sample set and were replicated at nominal significance level in a
second dataset.
Conclusions: Biological understanding of genetic variants could
lead to new understanding of GWAS data, and to the discovery of
novel disease risk genes.

S4.4 WHOLE GENOME SEQUENCING OF INDIVIDUALS
FROM THE PORTUGUESE ISLAND COHORT (PIC)
A. Fanous(1,2,3,4), Z. Zhao(5), J. Sun(5), R. Amdur(1,2), O.
Evgrafov(4), A. Clark(4), H. Medeiros(4), M. Pato(4), C. Pato(4),
J. Knowles*(4)
1. 1Washington VA Medical Center 2. Georgetown University
School of Medicine 3. Virginia Commonwealth University School of
Medicine 4. Keck School of Medicine of the University of Southern
California 5. Departments of Psychiatry, Biomedical Informatics, and
Cancer Biology, Vanderbilt University Medical Center
*knowles@med.usc.edu
Introduction: We have piloted using whole genome sequencing
(PE100@32X) with Illumina DNA sequencers for one individual in
each of 23 multiplex PIC pedigrees segregating schizophrenia (n=17)
or bipolar disorder (n=5).
Methodology: These data were mapped with BWA, or PerM and
variants were called with SAMtools and GATK, and then annotated
with either SVA or ANNOVAR.
Results: Each individual has approximately 3.5 million SNPs, of
which ~100-120 are nonsense and ~10,000 are missense. Each
annotated sequence variation was then weighted by the familyspecific
evidence of linkage derived from an autosomal dominant,
affecteds only, analyses.
Conclusions: We will present the results of these analyses and the
plan for our future work.
23
S4.5 WHOLE METHYLOME STUDIES OF PSYCHIATRIC
CONDITIONS
E. van den Oord*, G. Rudolf, S. Nerella, J. Bukszár, A. Khachane,
J. McClay, K. Åberg
VCU
*ejvandenoord@vcu.edu
Introduction: Several challenges exist when performing DNA
methylation studies of psychiatric conditions. First, many of the
disease processes involve the brain. However, as the procurement of
brain tissue is not possible in (living) patients, we often have to
perform such studies in DNA from peripheral whole blood or
Epstein-Barr virus (EBV) transformed cell lines. Second, CpG sites
may not show inter-individual methylation variation in the tissue that
is being studied. These “non-variable” sites need to be eliminated
prior to analyses to avoid false discoveries and improve statistical
power to detect biologically relevant markers. A third challenge
involves the interpretation of significant associations between
methylation markers and case-control status. For example, an
association may be the results of the methylation marker affecting
disease susceptibility or could be “spurious” as a result of, for
instance, medication use. Finally, methylation studies have
historically been restricted to the study of CpG sites in a limited
number of candidate genes. However, to find methylation markers it
may be needed to screen all CpG sites across the entire methylome
for association with disease status.
Methodology: We focus on next-generation sequencing as a costeffective
approach for whole methylome studies. To process the
massive amount of data generated in such studies and address the
above mentioned concerns, we present a data analysis pipeline we
developed consisting of the following steps 1) alignment & basic QC,
2) estimation of methylation levels, 3) selection of methylation
variable sites, 4) annotation, and 5) association analyses. Our data
analysis pipeline is illustrated using a sample of 1,500 subjects + 75
technical replicates. To study the use of whole blood and EBV DNA
in methylation studies of psychiatric conditions, we compared 1)
whole methylome profiles in cortex, hippocampus, and whole blood
from 10 inbred mice and 2) whole blood and EBV DNA from 10
human subjects.
Results: Consistent with the literature, our estimator suggests that
over 80% of all CpG are methylated. However, only a proportion of
these sites show substantial inter-individual methylation variation in
whole blood and should be used in subsequent association studies.
We find evidence that methylation variable sites share bioinformatics
features and can be correlated across larger genomic regions.
Methylation levels can be measured reliably in whole blood and
methylation profiles in whole blood shows overlap with methylation
profiles in brain. Caution seems required when interpreting results
from methylation studies using EBV DNA.
Conclusions: Whole methylome studies of psychiatric conditions are
economically and technically feasible and offer great potential to
supplement tradition sequence based genetic studies.

S4.6 PATHWAY AND NETWORK ANALYSIS OF GWAS
AND RNA-SEQ FOR SCHIZOPHRENIA
Z. Zhao*(1), P. Jia(1), L. Wang(1), J. Sun(1), A. Fanous(2,3), J.
Xu(4), I. Consortium(5), K. Kendler(2), X. Chen(2)
1. Vanderbilt University 2. Virginia Commonwealth University 3.
Washington VA Medical Center 4. SUNY at Buffalo School of
Medicine 5. International Schizophrenia Consortium
*zhongming.zhao@vanderbilt.edu
Introduction: Genome-wide association studies (GWAS) have
become a popular approach for searching for common genetic
variants which increase susceptibility to complex diseases or traits.
At the transcriptome level, RNA sequencing (RNA-Seq) is rapidly
emerging as a powerful tool for identifying differentially expressed
genes in diseases. Recently, pathway or network-based analysis of
genomic datasets has emerged as an alternative but potentially
powerful approach to searching for disease causal genes, assuming a
complex disease might have resulted from a number of genes which
disrupt one or more pathways or protein complexes.
Methodology: We applied several pathway enrichment methods to
schizophrenia GWAS datasets including Gene Set Enrichment
Analysis (GSEA), hypergeometric test, and a generalized additive
model (GAM). At the network level, we developed a dense module
searching (DMS) method to identify candidate subnetworks or genes
for complex diseases by integrating the association signal from
GWAS datasets into the human protein-protein interaction (PPI)
network. Finally, we performed a preliminary pathway analysis of
schizophrenia RNA-Seq data.
Results: We found several pathways that were top ranked and likely
associated with schizophrenia by these methods. These pathways are
related to metabolism of glutamate, the process of apoptosis,
inflammation, and immune system. Our pathway analysis of RNA-
Seq data generally supported these findings, including the
identification of the cell adhesion molecules (CAMs) pathway. Our
DMS analysis of schizophrenia GWAS datasets successfully
identified 164 network module genes, 12 of which were significant
by meta-analysis after multiple testing correction.
Conclusions: Our analysis suggested pathway and network
approaches are promising in post-GWAS era and may complement
the original analysis of genomics datasets such as GWAS and RNA-
Seq. However, biases and challenges in these methods exist and
improvement of methods is expected.
24
SYMPOSIUM 5: APPLICATION OF EXOME SEQUENCING
TECHNOLOGIES TO AUTISM
S5.1 THE GENETIC ARCHITECTURE OF AUTISM
SPECTRUM- AND RELATED- NEURODEVELOPMENTAL
DISORDERS REVEALED THROUGH HIGH-RESOLUTION
GENOME ANALYSIS
S. Scherer*
Hospital for Sick Children and University of Toronto
*stephen.scherer@sickkids.ca
We will provide an update of our Canadian efforts aimed at
cataloguing all highly-penetrant copy number variation (CNV) and
DNA sequence-level variants in autism spectrum and related
neurodevelopmental disorders. We are using the highest-resolution
genomic technologies to (i) examine a new Ontario-wide ASD
consecutive case cohort for the impact of CNVs in autism and related
neurodevelopmental disorders for diagnostic validity assessment and
discovery and (ii) through next generation sequencing (NGS) define
the allelic 'mutation' architecture in ASD creating a resource for
translational research and validated diagnostics.
We will present our latest data from the first few hundred sequenced
exomes/genomes describing both characteristic and new findings. We
will discuss our NGS sequencing on individuals carrying potentially
pathogenic large CNVs under the hypothesis that there may be
additional sequence changes or other contributing loci. Further
characterization of the variants identified is achieved by assessment
of segregation in families and by determining frequencies in
independent case and control populations, as well as through
functional studies.
We speculate that our approach will not only yield novel genes and
variants influencing ASD susceptibility, but will also shed light on
the broader issues of allelic variant architecture, variable penetrance
and expressivity, and phenotypic heterogeneity in complex
disorders. Some novel ‘pathogenic’ variants have been identified and
will this data will be presented at the meeting. We will also discuss
our experiences within a social health care system in translating this
information back to the participating families.

S5.2 EXOME SEQUENCING OF AUTISM AND
SCHIZOPHRENIA IN THE UK10K PROJECT
J. Barrett, A. Palotie*
The Wellcome Trust Sanger Institute
*ap8@sanger.ac.uk
Introduction: The UK10K project aims at sequencing 10 000
individuals to provide a catalogue of low frequency variants and to
study their association to disease traits. The project will generate
low-coverage (6X) whole genome sequences for 4000 individuals
from two deeply phenotyped UK population based cohorts, and deep
whole exome sequences for 6000 individuals with extreme clinical
phenotypes related to obesity, neurodevelopmental disorders and 8
rare severe diseases.
Methodology: We will describe the neurodevelopmental arm of the
project, which will sequence 3000 cases with autism or schizophrenia
in total. Approximately 800 non-syndromic autism spectrum disorder
cases have been selected from three UK and two Finnish centres.
These cases have been weighted in favor of a number of “high value”
criteria, including multiply affected families, and depth of additional
phenotype data
Results: Among the first cases being sequenced are a number of
large Finnish families with multiple affected individuals. We plan to
use genome-wide SNP data generated in these families to combine
exome sequence data with gene flow within families (i.e. withinfamily
linkage) to prioritize potential family specific high-penetrance
autism variants
Conclusions: A progress report of this startegy will be presented.
25
S5.3 WHOLE-EXOME SEQUENCING IN SIMPLEX AUTISM
QUARTETS
S. Sanders, M. Murtha, A. Gupta, J. Murdoch, M. Roubeson,
M. State*
Yale University School of Medicine
*matthew.state@yale.edu
Introduction: Over the last several years, the importance of rare
mutation for the genetic etiology of autism spectrum disorders (ASD)
has been repeatedly demonstrated. Recent studies comparing affected
to unaffected siblings within simplex families ascertained as part of
the Simons Simplex Collection (SSC) (Sanders et al 2011) has
confirmed and extended prior reports of the significant contribution
of large, de novo copy number variations (CNVs). These findings
have pointed to the marked effect sizes carried by de novo variants,
with odd ratios approaching 6 for the overall class of mutation, as
well as to the particular importance of specific regions of recurrence,
with population frequencies in affected individuals in some intervals
reaching 1%. Overall, from our empiric CNV data in more than 1000
SSC families, we have estimated the presence of 250 de novo genic
CNV regions carrying risk in the human genome, the vast majority of
which have not yet been identified. Whole- exome sequencing within
this same SSC cohort provides a highly efficient means to pursue
these findings in greater depth, offering to further elaborate the
genomic architecture of de novo variations in discordant sibling pairs
and to identify, via multiple recurrences within a given gene, specific
mutations contributing to ASD.
Methodology: We have undertaken whole-exome sequencing of 268
individuals from within 70 families ascertained by the Simons
Simplex Collection, a comprehensively phenotyped simplex cohort,
where the majority of pedigrees include a proband, an unaffected
mother and father and an unaffected sibling. The sequenced cohort
included 12 parent-child trios and 58 “quartets”, with the latter
providing a direct comparison of de novo mutation rates in matched
discordant sibling pairs. Within these 58 families, 11 carried
previously identified ASD-risk CNVs. Within the additional 12 trios,
4 carried established ASD risk CNVs, allowing for an assessment of
the relationship of de novo structural and sequence variation within
individuals and across the cohort. DNA selection was carried out
using either the Nimblegen custom whole-exome (35Mbp target) or
SeqCap EZExome v2 array (45Mbp target) and samples were
sequenced on either an Illumina GAIIx or Illumina HiSeq 2000
instrument
Results: We will first provide an overview of the alignment, variant
calling and quality control procedures for our whole exome data. We
will then present data on the overall burden of rare de novo
mutations, comparing affected individuals to their unaffected
siblings. We will address the question of recurrence of de novo
variants and their statistical significance in assessing association
Conclusions: Whole exome sequencing in simplex quartets with
ASD provides an important opportunity for gene discovery,
reaffirmes the contirbution of de novo variation to ASD, and provides
insight into the frequency, distribution, and character of de novo
sequence mutation in both affected and unaffected individuals.

S5.4 FULL EXOME SEQUENCING OF AUTISM CASES,
FAMILIES, AND CONTROLS
ECIP
B. Neale*(1,2), J. Buxbaum(3), B. Devlin(4), G. Schellenberg(5), J.
Sutcliffe(6), R. Gibbs(7), M. Daly(1,2)
1. Analytic and Translational Genetics Unit, Massachusetts General
Hospital 2. Program in Medical and Population Genetics, Broad
Institute of MIT and Harvard 3. Mount Sinai School of Medicine 4.
Department of Psychiatry, University of Pittsburgh 5. Department of
Pathology and Laboratory Medicine, University of Pennsylvania 6.
Department of Molecular Physiology and Biophysics, Vanderbilt
University 7. Baylor College of Medicine
*bmneale@gmail.com
Introduction: We conducted whole-exome sequencing on a case
control cohort of approximately 1,000 cases and 1,000 controls for
autism.
Methodology: For half of these samples, data were generated at
Baylor College of Medicine, using Nimblegen capture and ABI Solid
Sequencing and the other half were generated at the Broad Institute
of MIT and Harvard using Agilent capture and Illumina GAII and
HiSeq technologies. We will describe the alignment, variant calling
and general quality control analyses of both of these datasets
including a description of the relative merits of both capture and
sequencing technologies. As part of our study design, we have
sequenced a handful of samples at both centers, enabling a more
comprehensive comparison of genotype calls. We will also
demonstrate that these two datasets are largely comparable in terms
of more common variation, indicating that even though the entire
data generation pipeline is radically different between these two sites,
the assessment of common variation shows striking consistency.
Results: We have conducted a range of association tests on these two
datasets including variant-specific and gene-based approaches. For
variant-specific analyses, we test variation that is too rare to have
been effectively captured using genome-wide association (i.e.
frequency < 5%), with a particular focus on obviously functional
variation. For gene-based analysis, we have calculated burden of
nonsense and missense mutations for autism as well as applied Calpha
approach. We demonstrate that the genetics for autism must be
complex from the case-control analysis.
Conclusions: In addition to the case-control sequencing, we have
also generated data on 100 trios, which enables the assessment of de
novo mutations for risk to autism. We identified de novo mutations at
approximately the rate of 1 per trio and that these mutations follow a
Poisson distribution across the families analyzed. We have assessed
the extent to which the genes that carry de novo mutations are
excessively connected via protein-protein interactions.
26
SYMPOSIUM 6: BIOLOGICALLY INFORMED ANALYSIS
OF GWAS DATA: FROM BIOLOGY TO GENES AND BACK
S6.1 INFERENCE OF FUNCTIONAL GENE NETWORKS IN
THE SYNAPSE
L. Cornelisse*(1), E. Tsivtsivadze(2), T. Dijkstra(2,3), T. Heskes(2),
M. Verhage(1)
1. Functional Genomics, Center for Neurogenomics and Cognitive
Research (CNCR), Dept. of Clinical Genetics, VUmc, Neuroscience
Campus Amsterdam (NCA), VU University (VUA) and VU
University medical center (VUmc) 2. Machine Learning Group,
Intelligent Systems, Institute for Computing and Information
Sciences, Radboud University 3. Signal Processing Systems, Dept of
Electrical Engineering, Technical University Eindhoven
*niels.cornelisse@cncr.vu.nl
Brain disease is one of the most pressing health problems in today's
western society. For most brain disorders heritability estimates are
known to be high, (e.g. 90% for autism, 80% for schizophrenia).
However, the genetic variants identified so far with genome-wide
association studies (GWAS) explain only a small percentage of the
trait variance. One explanation of this 'missing heritability' is that
epistatic interactions between multiple genes have a major
contribution to the disease risk. These interactions will be undetected
due to necessary multiple testing corrections when 500,000+ genetic
variants are tested in parallel in a GWA approach. An alternative way
to model multiple small genetic effects and consider dependency
between different genes is to evaluate the combined, additive effects
of variations in multiple genes by means of pathway or functional
gene group analysis. Such a systems level approach relies heavily on
sound characterization of gene network architecture and the
functional interactions in the network. We focus on genes expressed
in synapses, which are small structures in the brain of about 1 µm 3 in
size with a crucial role in basic brain functions such as information
processing, learning and memory. About 10% of all genes is
expressed in the synapse of which several have been implicated in
neurological disorders over the past few years. We use machinelearning
techniques to infer functional gene networks in the
presynaptic terminal, which is responsible for the precisely timed
release of neurotransmitter during neuronal activity. High-content
immunoprecipitation mass spectrometry (IP-MS) interaction data
generated in our institute and functional data from genetic
perturbation studies in Hippocampal autaptic neurons (a reduced
model system for assessing synaptic transmission) are used to cluster
presynaptic genes in functional groups and pathways. We show that
presynaptic genes do not cluster exclusively to one pathway but can
be involved in multiple steps in the release process, which argues for
weighted functional grouping of genes in GWAS of complex traits.

S6.2 GENE-SET ENRICHMENT AND NETWORK-BASED
MULTI-LOCUS ANALYSES OF GENOME-WIDE DATA
P. Lee, D. Ruderfer, C. O'Dushlaine, S. Purcell*
Massachusetts General Hospital
*shaun@atgu.mgh.harvard.edu
Introduction: Under models of multifactorial inheritance a
considerable number of variants individually explain very little of the
total genetic variation in the population and therefore are hard to
detect. In this case, it will often be necessary to approach genomewide
datasets (whether of common single nucleotide polymorphisms
(SNPs), rare copy number variants (CNVs) from genome-wide
association studies (GWAS), or rare variants from whole-exome
sequencing studies) from a multilocus perspective, considering the
patterns of association to disease in the context of their genomic and
functional locations.
Methodology: We present two approaches that layer prior biological
information, in the form of either gene-sets or networks, onto the
otherwise functionally agnostic statistical information arising from
standard genotype-phenotype correlational analyses. We give an
overview of both methods and discuss alternatives.
Results: The first approach is designed to test for specific sets of
genes that are enriched in associated intervals in the context of
GWAS and CNV studies, and implemented in the INRICH software
package. We review applications of this approach across a range of
different (psychiatric and non-psychiatric) GWAS and discuss the
implications for likely genetic models and the adequacy of existing
“pathway” data for neuropsychiatric research. We also focus on the
utility of this approach to perform in silico fine-mapping in regions
where multiple genes contain variants in strong linkage
disequilibrium and are therefore supported by equally strong
association evidence The second approach utilizes biological network
information, for example, from databases such as the STRING
protein-protein interaction database, to guide gene-based rare variant
analyses of whole-exome sequence datasets. Gene-based association
tests for individual genes “borrow strength” from the statistics for
other genes that are neighboring in biological network space. This
approach is currently being implemented in the PLINK/Seq software
package.
Conclusions: As well as potentially adding biological insight on top
of genetic findings, consideration of biological information in
multilocus genetic analysis can be used to a) prioritize sub-threshold
associations from GWAS for follow-up, b) identify genes of small
effect, particularly apt for the analysis of very rare variants and c)
effectively perform in silico mapping of associated GWAS regions or
genes under large CNVs. We provide free, robust software packages
that can be used towards these aims.
27
S6.3 PROTEIN COMPLEXES AND THE FUNCTIONAL
BASIS OF PSYCHIATRIC DISORDERS
A. Pocklington*
Cardiff University
*pocklingtonaj@cardiff.ac.uk
Introduction: To identify cellular processes disrupted in psychiatric
disorders and understand the impact of disease-associated mutations
will require appropriate models of functional organisation at the
molecular level. A common mechanism of organisation found in all
cell-types is the physical localisation of molecules to form specialised
functional components.
Methodology: Proteomic characterisation of organelles and protein
complexes can be used to generate a high-level model of the cellular
machinery suitable for gene-set/pathway based analyses. In addition
to providing a very clear link to cell-biological function, such models
can drastically reduce the burden of multiple testing, a major problem
associated with the fine-grained functional ontologies used to date.
Results: This presentation will concentrate on proteomic studies of
the synapse, being the major component of the cellular machinery
unique to the nervous system.
Conclusions: Current models of synapse molecular organisation will
be described and their relevance to psychiatric genetics discussed.

S6.4 THE USE OF PROTEIN-PROTEIN INTERACTIONS TO
INTERPRET GENETIC ASSOCIATION TO DISEASE
ECIP
E. Rossin*(1,2,3), K. Lage(4), S. Ripke(1,2), B. Neale(1,2), K.
Samocha(1,2,3), P. GWAS Consortium(1,2,3), S.
Raychaudhuri(2,3,5), R. Xavier(1,2,3), C. Cotsapas(2,6), M.
Daly(1,2,3)
1. Massachusetts General Hospital 2. The Broad Institute 3. Harvard
Medical School 4. Center for Biological Sequence Analysis,
Department of Systems Biology, Technical University of Denmark 5.
Brigham and Women's Hospital 6. Yale School of Medicine
*rossin@broadinstitute.org
Introduction: Genome-wide association studies (GWAS) have
defined hundreds of genomic regions containing variation
predisposing to complex disease. Inferring disease biology from these
observations, however, hinges on our ability to discover the
molecular processes being perturbed by these risk variants. It has
previously been observed that different genes harboring causal
mutations for the same Mendelian disease often physically interact.
In a pursuit to evaluate the degree to which this is true of genes
within strongly associated loci in complex disease as well as genes
identified through more recent exome sequencing as potentially
baring risk mutations, we have developed a method called DAPPLE
(Disease Association Protein-Protein Link Evaluator).
Methodology: Using a collection of 170,000 published proteinprotein
interactions, DAPPLE looks for direct and indirect
connections between proteins from associated loci to build a diseasespecific
network that includes not only the seeded proteins but also
proteins elsewhere in the genome. Because protein-protein interaction
data can be biased, we then evaluate the subsequent network and its
individual members for connectivity beyond chance expectation
using within-degree node-label permutation, an approach that
controls for the varying degree to which proteins are represented in
the database. We then look for enrichment in various external
properties in the network, such as association to phenotype or
particular genes of interest. We looked for protein-protein
interactions within the top hits in a recent schizophrenia metaanalysis
(9394 cases, 12462 controls) as well as de novo mutations
(missense, nonsense or splice-site) from an on-going autism exome
sequencing study (100 trios).
Results: In schizophrenia, we find that the emergent network from
the top associations is enriched for the predicted targets of mir-137, a
micro-RNA in one of top regions, and that those targets are also
enriched for association to Schizophrenia. In Autism, we find that the
network built from genes harboring single de novo
missense/nonsense/splice-site mutations show direct and indirect
connections far in excess of chance.
Conclusions: We have developed a method to systematically look
for protein-protein interactions between proteins from genomic loci
of interest and evaluate subsequent networks for statistical
enrichment in connectivity. We have shown that when applied to
schizophrenia and autism, such a method can be useful to identify
potentially important biochemical connections.
28
S6.5 EXPLORING GENOME-WIDE ASSOCIATION DATA IN
BIOLOGICAL CONTEXT THROUGH PROTEIN-PROTEIN
INTERACTIONS
P. Sham*, J. Kwan, M. Li
The Universiy of Hong Kong
*pcsham@hku.hk
Introduction: In recent years, gene-based tests have gained
popularity in genome-wide association studies (GWAS), because the
gene is generally regarded as the basic functional unit of the genome.
However, genes code for proteins which often interact physically
with each other to form more complex functional structures. A
natural generalization of gene-based analysis is therefore the
consideration of gene sets that code for interacting proteins.
Methodology: We have developed an association test for the simple
scenario, of protein-protein interaction (PPI) pairs. This test considers
all PPI pairs from public databases for evidence of association
between sequence variants in both genes, through the combination of
gene-based statistics. The test assigns differential weights to the two
genes in a PPI pair according to their numbers of PPI partners, and
filters out significant pairs where all the evidence for association
comes primarily from only one of the two PPI partners.
Results: The new test was applied to a published GWAS on Crohn’s
disease, and detected a number of PPI gene pairs significantly
associated with disease, even after Bonferroni adjustment for the total
number of PPI pairs. Among these significant pairs are those where
one or both partners are not significant according to gene-based tests.
Conclusions: We conclude that association analysis of PPI pairs is a
useful complement to SNP-based and gene-based analyses, and may
provide additional statistical power for detecting genes associated
with complex diseases. This may be particularly useful for
psychiatric disorders because of the small effect sizes of the SNPs
that so far have been detected.

SYMPOSIUM 7: FROM GENES TO BIOLOGY:
DEVELOPMENTAL PSYCHOPATHOLOGY
GENETIC EPIDEMIOLOGY OF ADHD AND DEPRESSION
ACROSS THE LIFESPAN
D. Boomsma(1), C. Middeldorp(1), C. Dolan(1), M. Nivard(1), K.
Kan(1), M. Groen-Blokhuis(1), J. van Beek(1), L. Geels(1), L.
Ligthart(1), J. Hudziak(1), R. Althoff(1), T. van Beijsterveldt(1), J.
Vink(1), M. Bartels(1), G. Willemsen(1), E. de Geus(1)
1. Netherlands Twin Register, Dept of Biological Psychology, VU
University 2. University of Vermont
Introduction: Large genome-wide association (GWA) studies of
complex psychiatric phenotypes need to consider whether effects of
genetic variants should be evaluated separately in men and women,
or as a function of age, as the effect of a particular variant may be
different across sex and age. Expression of genes can differ across
sex or age (genotype x sex and genotype x age interactions) but
increasing the number of tests amplifies the penalty for multiple
testing. We test for quantitative and qualitative sex and age
differences in genetic architecture for multiple indices of ADHD and
depression phenotypes using longitudinal data from same-sex and
opposite-sex twin pairs, age 3 through 80 years.
Methodology: The Netherlands Twin Register (NTR) has
collected longitudinal data in children from age 3 years up till age
20+ on multiple indices of Attention Problems and ADHD and
anxious depression by parental, teacher and self-report (N >
16.000 pairs). In adults, multiple inventories assessing these
phenotypes by self-report were collected between 1991 and 2011 (up
to 9 surveys; N >7500 adult twins). Longitudinal genetic analyses of
these data were performed with structural equation modeling.
Genomewide SNP typing is available in subgroups of participants.
Results: Longitudinal twin data on ADHD and depression show
heritabilities to be only mildly affected by rater or sex, but
significantly by age. Genetic correlations along the lifespan will be
presented, addressing whether the same genes are operating at all
ages.
29
S7.2 TWINS, TISSUE AND TIME: A COMPARISON OF
GENOMIC STRUCTURE ACROSS TWINS, DNA AND
LONGITUDINAL SAMPLES
P. Scheet*(1), E. Ehli(2,3), X. Xiao(1), A. Abdellaoui(3), R.
Althoff(4), J. Hottenga(4), G. Willemsen(4), K. Nelson(2), P.
Huizenga(2), Y. Hu(2), M. Bartels(4), M. Groen-Blokhuis(4), E. de
Geus(4), J. Hudziak(5), G. Davies(2,3), D. Boomsma(4)
1. Department of Epidemiology, University of Texas M. D. Anderson
Cancer Center 2. Avera Institute for Human Behavioral Genetics,
Avera McKennan Hospital and University Health Center 3.
Department of Psychiatry, University of South Dakota, Sanford
School of Medicine, Division of Basic Biomedical Sciences 4.
Department of Biological Psychology, VU University 5. Department
of Psychiatry, University of Vermont, College of Medicine
*pscheet@alum.wustl.edu
Introduction: With the desire to assess genetic variation with
conveniently-obtained biological sources in large scale collaborative
projects, one question is whether inference of copy number (CN) is
overly sensitive to the source of material for DNA analysis (e.g.
blood, buccal) and another is whether CN is stable over time. Here,
we address these questions by studying 1,471 DNA samples from
710 individuals in the Netherlands Twin Register, including both
twins and non-twins, with the availability of longitudinal samples and
samples from different tissues, to obtain a technical evaluation and
confirmation of copy number inference from the Affymetrix 6.0
DNA microarray technology.
Methodology: We analyzed DNA from longitudinal blood and
buccal sources from a large sample (n = 710 subjects), including 43
MZ (23 female) and 75 DZ (26 both female, 23 both male), their
parents and siblings. The participants are registered with the
Netherlands Twin Register and DNA samples have been collected in
multiple projects, both from blood and buccal material. In addition,
we examine effects of plating individuals on the estimation of
CNVs. Finally, we aim to evaluate whether blood is an acceptable
DNA source in studies that include twins. To assess the consistency
of CN inference across DNA source material, blood and buccal
derived samples from the same individuals were compared (withinindividual,
between sources) and from different members of the same
MZ pair. To assess the consistency over time, samples of the same
individual and tissue type, obtained at different time points, were
compared. Multiple algorithms were applied to obtain CNV
calls. We focus on those from Birdsuite v.2 (Korn et al).
Results: No greater discordance was found for CN and genotype
inference between samples from the same individual (or MZ cotwin)
that derived from buccal than from blood. However, there was a
small but statistically-significant decrease in across-tissue
concordance. We also found no evidence of a temporal effect on CN
variation from 389 individuals sampled at 2 time points ranging from
1 to 12 years apart. Copy number estimates between co-twins from
43 MZ pairs were highly consistent for both deletions (R 2 ≈ 90%) and
duplications (R 2 ≈ 86%), as was genotype concordance (R 2 > 99%).
Conclusions: In light of our data and results, we feel it is prudent,
and indeed cost-effective, to conduct a microarray-based GWA study
of genotypes and copy number using buccal-derived DNA for efforts
to map genetic variants predisposing to disease and behaviors. This
allowance will lower the barrier for participation of many groups of
individuals, including children. Finally, our study confirms that
collections of blood derived DNA from large twin registries offer a
valuable resource for mapping and characterizing complex disease,
given their unique contribution to partitioning environmental and
genetic effects and the stability of genomic features across samples
and time.

S7.5 FURTHER UNDERSTANDING THE HETEROGENEITY
OF MDD
B. Penninx*
VU University Medical Center, department of Psychiatry
*b.penninx@vumc.nl
Introduction: MDD is a highly heterogeneous disorder, which limits
the search for genetic predictors.
Methodology: Using GWA from the NESDA study, we examined
whether evidence can be found for differential genetic predictors for
chronic versus non-chronic depression using 2-year longitudinal data.
Results: Results will be presented from GWA and candidate gene
analyses on genetic predictors of the course of depression. For this
purpose we will use the 2-year longitudinal data from more than 1000
MDD cases from the NESDA study in which course trajectories were
assessed.
Conclusions: Acknowledging the heterogeneity of MDD, it is
essential to further examine the differential genetic predictors of
MDD subtypes.
30
SYMPOSIUM 8: ELUCIDATING THE FUNCTIONAL
RELEVANCE OF THE ANK3 AND CACNA1C BIPOLAR
DISORDER RISK GENES
S8.1 ANKYRIN G AND L-TYPE CALCIUM CHANNEL:
POTENTIAL ROLES IN PSYCHIATRIC DISEASE
S. Zhu(1), V. Bennett(2), C. Ross*(1)
1. Johns Hopkins 2. Duke
*caross@jhu.edu
Introduction: Ankyrin G is one of the strongest genetic risk factors
identified by GWAS for bipolar disorder. In brain, it mainly localizes
at the axon initiation segment (AIS) and Node of Ranvier. Cav1.2,
the alpha subunit of L-type voltage gated calcium channel, is a risk
factor by GWAS for bipolar disorder and schizophrenia. We are
exploring the effects of loss of Ankyrin G function, and since
Ankyrin G can bind to several other ion channels, we postulated that
it could also interact with the calcium channel.
Methodology: We are using cellular and molecular techniques both
in vitro and in vivo
Results: Immunoprecipitation from SH-SY5Y cells transfected with
Ankyrin G and Calcium channel constructs indicates an interaction
mediated by the beta subunit. Double label immuno-fluorescence
studies in primary cultured neurons and mouse brain sections suggest
partial colocalization. We are probing the cellular significance of loss
of function of Ankyrin G and interactions between Ankyrin G and
Ca v1.2, by knockdown of Ankyrin G in neuronal cell lines and
primary neurons. Bipolar disorder and schizophrenia are believed to
involve dysregulation of brain development. Ankyrin G is known to
regulate the innervation of inhibitory interneurons of the AIS of
cerebellar Purkinje cells. We are examining the effect of knockdown
of Ankyrin G on interneuron innervations of pyramidal cells in the
developing cerebral cortex. We are also characterizing Ankyrin G
loss of function in a novel conditional mouse model, and using in
utero elctroporation.
Conclusions: These studies suggest a role for Ankyrin G and its
protein interactions in cellular pathogenic pathways and cortical
development, which may provide possible therapeutic targets for
psychiatric disorders.

S8.2 ROLE OF ANKYRIN 3 IN REGULATING BIPOLAR-
RELATED BEHAVIORS
M. Leussis(1,2,3), E. Berry-Scott(3), H. Jhuang(4), M. Saito(2), K.
Ilsley(2), T. Poggio(5), P. Sklar(6), T. Serre(4), T. Petryshen*(1,2,3)
1. Dept of Psychiatry, Massachusetts General Hospital and Harvard
Medical School 2. Psychiatric and Neurodevelopmental Genetics
Unit, Center for Human Genetic Research, Massachusetts General
Hospital 3. Stanley Center for Psychiatric Research, Broad Institute
4. Cognitive, Linguistic & Psychological Sciences Dept & Institute
for Brain Sciences, Brown University 5. McGovern Institute for
Brain Sciences, MIT 6. Mount Sinai School of Medicine
*petryshen@chgr.mgh.harvard.edu
Introduction: The ankyrin 3 gene (ANK3) has been conclusively
identified as a risk gene for bipolar disorder (BD) in numerous
patient GWAS and targeted association studies. ANK3 encodes the
ankyrin G scaffolding protein that functions in the development and
maintenance of the axon initial segment (AIS) of neurons that elicits
action potentials, as well as maintenance of neuronal polarity and
synaptic function. The mechanism by which ANK3 contributes to
BP risk is unknown. As a first step towards elucidating this
mechanism, we are investigating the behavioral and neurobiological
impact of dysregulated neural expression of mouse Ank3 using RNA
interference and knockout genetic models.
Methodology: Lentiviral-mediated RNA interference was used to
reduce Ank3 expression in hippocampus or nucleus accumbens of
adult male C57BL/6J mice. Lentivirus expressing a GFP marker and
one of two short hairpin RNA (shRNA) sequences targeting Ank3, or
a scrambled control sequence, was injected bilaterally (≥10 9 infection
units/ml) into hippocampus or nucleus accumbens (N = 10-12 mice
per group). Mice were assessed for behaviors modeling bipolar
disorder symptoms, including novelty- and psychostimulant-induced
hyperlocomotion, behavioral disinhibition, and hedonic and
anhedonic behaviors, as well as intermediate phenotypes (prepulse
inhibition), circadian activity, learning (fear conditioning,
habituation), and sensory and motor performance. Reversal of the
behavioral phenotype was examined following chronic treatment
with lithium (85 mg/kg i.p.) or lamotrigine (2.5 mg/kg i.p.). To
validate findings from RNA interference, knockout mice with Ank3
haploinsufficiency in brain were assessed for a subset of
behaviors. Expression of ankyrin G and protein interactors was
measured by immunohistochemistry of fixed brain to evaluate the
impact of Ank3 reduction on neural functions.
Results: Mice with hippocampal Ank3 silencing displayed consistent
changes in several behaviors for both shRNA sequences (P < 0.05 vs.
control shRNA), while other behaviors were unchanged, indicating
the phenotype is not due to global impairment. Lithium treatment
partially reversed some behavioral changes, whereas lamotrigine had
a non-specific effect on the Ank3 and control shRNA groups. By
immunohistochemistry, both Ank3 shRNA sequences reduced
ankyrin G expression at the AIS by 40-50%, suggesting impaired
action potential firing may underlie the behavioral changes, although
other Ank3 functions could also be perturbed. Ank3 silencing in
nucleus accumbens resulted in less robust behavioral changes,
potentially due to insufficient virus distribution in this region.
Conclusions: Viral-mediated RNA interference in mouse brain is a
practical method for studying the neural function of psychiatric risk
genes. The behavioral changes induced by Ank3 hippocampal
reduction and their reversal by lithium treatment in mice suggest that
the mechanism by which ANK3 confers BD risk is through a loss of
function. These results and ongoing work defining the neural
aberrations underlying the behavioral changes are expected to help
elucidate the disease relevance of ANK3.
31
S8.3 MOOD DISORDER SUSCEPTIBILITY GENE CACNA1C
MODIFIES MOOD-RELATED BEHAVIORS IN MICE AND
INTERACTS WITH SEX TO INFLUENCE BEHAVIOR IN
MICE AND DIAGNOSIS IN HUMANS
T. Gould*(1), D. Dao(1), P. Mahon(2), X. Cai(1), C. Kovacsics(1),
D. Levinson(3), M. Arad(1), J. Shi(3), P. Zandi(2), J. Knowles(4), M.
Weissman(5), W. Coryell(6), W. Scheftner(7), W. Lawson(8), S.
Thompson(1), J. Potash(2)
1. University of Maryland School of Medicine 2. Johns Hopkins
University 3. Stanford University 4. University of Southern
California 5. Columbia University 6. University of Iowa 7. Rush
University 8. Howard University
*gouldlab@me.com
Introduction: Recent genome-wide association studies have
associated polymorphisms in the gene CACNA1C, which codes for
CaV1.2, with a bipolar disorder and depression diagnosis.
Methodology: The behaviors of wild-type and Cacna1c
heterozygous mice of both sexes were evaluated in a number of tests.
Based upon sex differences in our mouse data, we assessed a
geneXsex interaction for diagnosis of mood disorders in human
subjects. Data from the NIMHBP and the GenRED Consortiums
were examined using a combined dataset that included 2021 mood
disorder cases (1223 females) and 1840 controls (837 females).
Results: In both male and female mice, Cacna1c haploinsufficiency
was associated with lower exploratory behavior, decreased response
to amphetamine, and antidepressant-like behavior in the forced swim
and tail suspension tests. Female, but not male, heterozygous mice
displayed decreased risk-taking behavior or increased anxiety in
multiple tests, greater attenuation of amphetamine-induced
hyperlocomotion, decreased development of learned helplessness,
and a decreased acoustic startle response, indicating a sex-specific
role of Cacna1c. In humans, sex-specific genetic association was seen
for two intronic single nucleotide polymorphisms, rs2370419 and
rs2470411, in CACNA1C, with effects in female subjects (odds ratio
= 1.64, 1.32) but not in male subjects (odds ratio = .82, .86). The
interactions by sex were significant after correction for testing 190
single nucleotide polymorphisms (p(corrected) = .03, .04) and were
consistent across two large datasets.
Conclusions: Our preclinical results support a role for CACNA1C in
mood disorder pathophysiology, and the combination of human
genetic and preclinical data support an interaction between sex and
genotype.

S8.4 IMPACT OF THE PSYCHIATRIC SUSCEPTIBILITY
GENE CACNA1C IN HUMAN IMAGING GENETIC STUDIES
ON NEURAL ACTIVITY IN HEALTHY SUBJECTS - AN
OVERVIEW
S. Witt*(1), J. Strohmaier(1), S. Erk(2), A. Krug(3), M. Thimm(3),
C. Kuehner(4), T. Schulze(5), T. Kircher(1), H. Walter(2), M.
Wessa(2), M. Rietschel(1)
1. Department of Genetic Epidemiology in Psychiatry, Central
Institute of Mental Health, University of Heidelberg 2. Neurology,
Neurosurgery and Psychiatry, Division of Mind and Brain Research,
Charité 3. Department of Psychiatry and Psychotherapy, Philipps-
University 4. RG Longitudinal and Intervention Research, Dep of
Psychiatry and Psychotherapy Institute of Mental Health, University
of Heidelberg 5. Clinic for Psychiatry and Psychotherapy, Georg-
August-University 6. Department of Cognitive and Clinical
Neuroscience, Institute of Mental Health, University of Heidelberg
*stephanie.witt@zi-mannheim.de
Introduction: Recent genome-wide association studies report strong
evidence for an association between the single nucleotide variant
rs1006737 in CACNA1C and bipolar disorder, schizophrenia, and
major depression. The impact of this risk variant has been tested
since in endophenotype studies using an imaging genetics approach
in healthy individuals – a strategy which has repeatedly proven to be
successful as it is not hampered by confounding variables that are
typically present in patients.
Methodology: This presentation gives an overview on imaging
genetic studies which analyzed association of rs1006737 with
endophenotypes from functional MRI studies carried out in the
Department of Genetic Epidemiology together with different clinical
collaboration partners with sample sizes ranging between 63 and 110
participants. Studies vary with regard to the functional MRI
paradigms which were applied in the specific contexts.
Results: Brain functions associated with the genetic variant include
neural activity related to episodic memory, attention networks, verbal
fluency and reward circuits. Differential activation with regard to
rs1006737 is found in different regions of the brain including
hippocampus, amygdala, frontal and temporal gyrus and precuneus.
Moreover, we will give an outlook on association of rs1006737 with
behavioral and personality measurements.
Conclusions: The results of our studies are put into context with
other recent imaging genetic studies on rs1006737 from the literature.
32
S8.5 HUMAN FUNCTIONAL STUDIES OF ANK3 AND
CACNA1C FROM THE GREEK LOGOS COHORT
P. Bitsios*(1), P. Roussos(1,2), S. Giakoumaki(1), M. Pasparakis(1)
1. Department of Psychiatry and Behavioral Sciences, University of
Cretel 2. Department of Psychiatry, Mount Sinai School of Medicine
*pbitsios@med.uoc.gr
Introduction: The rs1006737 CACNA1C and rs10994336 ANK3
genetic variants have been recently identified as the most consistent,
genome-wide significant risk factors for bipolar disorder, while the
CACNA1C variant has also been associated with schizophrenia and
major depression. Genetic association studies in confounder-free,
healthy subjects using multiple disease endophenotypes is a useful
strategy that may elucidate the functional role of GWAS-supported
risk polymorphisms and, in particular, the mechanism by which they
increase risk for mental illness.
Methodology: We examined the phenotypic consequences of these
risk alleles in a large homogeneous cohort of healthy young males
(n=543 mean age 22.1±3) recruited from the first wave of the
LOGOS project (Learning On Genetics Of Schizophrenia) in
Heraklion, Crete. Subjects were tested for sensorimotor gating as
assessed by prepulse inhibition (PPI), working and verbal memory,
executive function, startle reactivity and temperament and personality
traits. A subsample of 220 subjects underwent testing for affective
startle modulation using the IAPS (International Affective Picture
System).
Results: UNPHASED analysis revealed that the CACNA1C risk
allele (rs1006737_A) was associated with lower extraversion and
higher harm avoidance, trait anxiety and paranoid ideation consistent
with a non-specific proneness to anxiety and paranoia, while the
ANK3 risk allele (rs10994336_T) was associated with lower novelty
seeking and behavioral response to reward, consistent with proneness
to anhedonia. Both risk alleles were associated with high startle
reactivity. CACNA1C risk allele carriers also presented with
enhanced startle reactivity in the aversive-pictures condition. The risk
genotypes did not affect sensorimotor gating, working memory or
executive function in this cohort of healthy males.
Conclusions: The personality configuration and affective startle
reactivity data suggest that these GWAS-supported risk
polymorphisms are associated with emotional dysregulation,
penetrant in otherwise asymptomatic and apparently cognitively
intact individuals. At least as far as the CACNA1c variant is
concerned this is in keeping with recent reports suggesting a role of
this variant in abnormal threat signal processing within the
hippocampus and/or amygdala which may lie in the causal pathway
that links genetic risk to affective illness, or indeed, schizophrenia.
The relative risk and the environmental/epistatic conditions required
for the conversion of risk allele carriers to mild symptomatic stages
and/or to overt illness need to be assessed in longitudinal designs.
This strategy may facilitate early, effective and cost-efficient
genotype-dependent therapeutic interventions.

SYMPOSIUM 9: ADVANCES IN UNDERSTANDING
DYSBINDIN-1 FUNCTIONS RELEVANT TO
SCHIZOPHRENIA
S9.1 REGULATION OF SYNAPSE COMPOSITION BY THE
DYSBINDIN ASSOCIATED COMPLEXES, BLOC-1 AND AP-3
V. Faundez*
Emory University
*vfaunde@emory.edu
Introduction: Dysbindin assembles into the biogenesis of lysosome
related organelles complex 1 (BLOC-1), which interacts with the
clathrin adaptor complex 3 (AP-3). Both complexes participate in a
common endosome trafficking route. Deficiencies in AP-3 and
BLOC-1 subunits affect synapse composition suggesting roles for the
two complexes in protein sorting to or from synapses.
Methodology: We tested this hypothesis by analyzing the targeting
of an AP-3 and BLOC-1-dependent membrane protein cargo targeted
to in pre and postsynaptic compartments, PI4KIIa.
Results: PI4KIIaco-purifies with BLOC-1 and AP-3 in neuronal
cells, an association sensitive to the BLOC-1 genetic dosage. These
biochemical interactions were corroborated genetically as since a
decreased PI4KIIacontent in the dentate gyrus neuropil of dysbindinnull
sandy mice was phenocopied in BLOC-1 subunit deficiencies,
pallid and muted, and the AP-3-null mocha allele. Reduction of
PI4KIIain the dentate reflects a failure to traffic from the cell body.
PI4KIIawas targeted to processes in wild type primary cultured
cortical neurons and PC12 cells, but failed to reach neurites in cells
lacking either AP-3 or BLOC-1 complexes. Similarly, disruption of
an AP-3 sorting motif in PI4KIIaimpaired its sorting into processes of
PC12 and primary cultured cortical neuronal cells.
Conclusions: Our findings indicate a novel vesicle transport
mechanism requiring dysbindin-associated complexes for cargo
targeting from neuronal cell bodies to neurites and nerve terminals,
and suggest that mistargeting of specific vesicular cargos may
underlie, in part, the molecular pathogenesis of schizophrenia
33
S9.2 EPISTATIC INTERACTIONS BETWEEN DTNBP-1 AND
COMT: EFFECTS ON WORKING MEMORY IN MICE AND
PREFRONTAL PHYSIOLOGICAL ACTIVITY IN HUMANS
D. Weinberger*, F. Papeleo, G. Carr, J. Chen, M. Burdick, R.
Straub, J. Callicott
NIMH/NIH
*weinberd@mail.nih.gov
Introduction: Psychiatric genes are involved in networks and
pathways that subserve risk relevant cell biology, and the risk valence
of a particular gene likely depends on the integrity of other related
proteins. DTNBP1 has been linked with DA synaptic activity via D2
receptor trafficking after ligand induced internalization, which has
been demonstrated in cell culture (Iizuki et al 2008) and in mice
(Yuanyuan et al 2009). We tested the cognitive effects of the
DTNBP1-DA interaction in mice and the cortical physiologic effects
in humans with fMRI by genetically varying dysbindin expression
and COMT enzyme activity.
Methodology: Based on the D2 trafficking effects and the well
characterized inverted U shaped DA response relationship in
prefrontal cortex, it was predicted that decreased dysbindin
expression and increased synaptic dopamine would translate into
abnormal D2 signaling which would be disadvantageous in both the
mouse and human paradigms. Single (COMT or DTNBP1) and dual
(COMT plus DTNBP1) C57 background knockout mice were created
(total N= 71 animals) and tested in the forced choice alternating T
maze working memory task. It was predicted that individual gene
alterations would enhance working memory, but combined defects
would diminish it. For the human fMRI experiment, normal subjects
(N=115) performed the N back working memory task. Similarly, it
was predicted that there would be nonlinear, epistatic effects of
COMT and DTNBP1 on physiological efficiency during working
memory task in normal subjects, associated with exaggerated D2
signaling. The effect of a DTNBP1 haplotype associated with
decreased expression of dysbindin in human prefrontal cortex (Bray
et al 2005) was tested on the background of COMT val/met
genotypes.
Results: Compared with wild type animals, each single KO mouse
required fewer days to achieve criteria, but the combined gene KO,
either combined heterozygotes or combined homozygotes, showed a
dramatic failure of learning the task (p

S9.3 DYSBINDIN-1 MODULATES BRAIN STRUCTURE,
GLUTAMATERGIC FUNCTION AND MEMORY IN MICE
J. Jentsch*(1,2)
1. Department of Psychology, UCLA 2. Department of Psychiatry &
Bio-behavioral Sciences, UCLA 3.
*jentsch@psych.ucla.edu
Introduction: Though dysbindin-1 has been repeatedly associated
with schizophrenia, much more needs to be learned about the specific
role the gene product plays in the pathogenesis of the disorder.
Fortunately, many of the biological roles and functional properties of
dysbindin-1 are conserved between mice and humans, permitting a
direct study of the cellular, network and systems abnormalities that
mediate mnemonic and cognitive deficits caused by functional
variation in the gene. Here, we take use of a genetic model of
dysbindin-1 deficiency in mice to explore the mechanisms by which
this gene affects memory-related systems, including the prefrontal
cortex and hippocampus.
Methodology: Mice carrying a spontaneous, null mutation of the
gene encoding dysbindin-1, on the C57Bl6 background, were used in
the studies. A combination of in vitro electrophysiological recordings
from prefrontal cortical and hippocampal neurons, in vivo
microdialysis studies, in vivo micro-magnetic resonance imaging
scans, ex vivo gene expression analyses and behavioral assessments
of memory function (delayed non-match-to-position, object/social
recognition, contextual fear conditioning) were used.
Results: Genetic dysbindin deficiency (including haploinsufficiency)
is associated with alterations in glutamatergic signaling. In vitro,
spontaneous and evoked excitatory post-synaptic currents are reduced
in prefrontal cortex and hippocampus a variety of evidence supports
the notion that this is due to compromised pre-synaptic release of
glutamate during sustained activity conditions. Additionally,
adaptations in post-synaptic gluamate receptor function (specifically,
NMDA/glutamate receptor hypoactivity) has been identified in both
regions, and this effect is at least in part transcriptional in nature. In
vivo, evoked gluamate release is - as expected - diminished. Finally,
functional activity within hippocampus and dopaminergic networks
has been identified with manganese-enhanced microMRI.
Collectively, these glutamatergic abnormalities within hippocampus
and prefrontal cortex combine to underlie complex memory systems
abnormalities, including difficulties with working memory, object
recognition and contextual fear learning.
Conclusions: A range of pre- and post-synaptic neuroadaptations
affecting glutamatergic transmission appear to be caused by genetic
deficiency in dysbindin-1 function. By identifying the proximal
changes in neurotransmission that are caused by reduced dysbindin-1
function and that link to the memory systems complications
stemming from neurochemical changes, rationale therapeutic
strategies can be developed.
34
S9.4 DYSBINDIN-1 MUTANT MICE IMPLICATE REDUCED
PARVALBUMIN-CELL MEDIATED INHIBITION AS A
FINAL COMMON PATHWAY IN THE
PATHOPHYSIOLOGY OF SCHIZOPHRENIA
K. Talbot*, G. Carlson, M. Gandal, R. Gur, S. Arnold, S. Siegel
University of Pennsylvania
*talbotk2@mail.med.upenn.edu
Introduction: At least twenty studies have reported an association
between schizophrenia and variation in the dystrobrevin binding
protein 1 gene (DTNBP1). An increasing number of studies report
that several of these DTNBP1 risk variants are associated with
severity of the disorder's positive and negative symptoms, as well as
its cognitive deficits. While the relationship of risk variants in
DTNBP1 and the expression of the encoded protein, dysbindin-1,
remains unclear, reductions in that protein appear to be a common
feature of synaptic tissue in at least three brain areas in
schizophrenia: auditory cortices, hippocampal formation, and
dorsolateral prefrontal cortex. Studies on sandy mice homozygous for
a deletion mutation in Dtnbp1 (dys -/-) resulting in loss of dysbindin-
1 have shown that this protein directly or indirectly regulates
glutamate, dopamine, and GABAergic transmitter systems. All of
those systems regulate cerebrocortical gamma-band oscillations,
which are generated by interactions among parvalbumin (PV) cell
networks and pyramidal cells. Abnormalities in gamma oscillations
are common features in schizophrenia and are associated (like
DTNBP1 risk variants) with the diagnostic symptoms and cognitive
deficits of the disorder. Since disruption of gamma oscillations may
be a final common pathway in the pathophysiology of schizophrenia,
we tested the effects of dysbindin-1 loss on auditory-induced gamma
activity, the PV cells and inhibitory drive critical to that activity, and
endophenotypes of schizophrenia associated with gamma activity.
Methodology: The auditory cortex and hippocampus of 12 male dys
-/- and 12 male wild-type littermates on a C57BL6/J background
were studied. PV cell populations in both areas were characterized
immunohistochemically. Auditory evoked response potentials were
recorded to study acoustic responses, sensory gating, and prepulse
inhibition (PPI) and later used in time-frequency analyses to evaluate
auditory evoked gamma oscillations recorded from the hippocampus.
Voltage-sensitive dye (VSD) imaging of hippocampal slice
preparations was used to study inhibitory drive in CA1 following
Schaffer collateral stimulation.
Results: While showing normal acoustic brain stem responses, dys -
/- mice displayed auditory endophenotypes of schizophrenia, namely
reduced sensory gating and PPI, both of which were correlated with
reduced power and phase-locking of evoked, early gamma activity.
The basis for these abnormalities was suggested by reduced PV
immunoreactivity in PV cells of the auditory cortex and hippocampus
in dys -/- mice. The potential impact of this abnormality in fastspiking
inhibitory neurons on gamma activity was shown by
markedly reduced inhibitory CA1 responses of dys -/- mice to
Schaffer collateral activation with no apparent effect on evoked
excitation.
Conclusions: These findings collectively indicate that dysbindin-
1 promotes generation of gamma oscillations by PV-pyramidal cell
networks and that disruption of that role promotes auditory
endophenotypes of schizophrenia potentially promoting both its
clinical symptoms and cognitive deficits. The same cell networks
may be a common target of other genetic risk factors for this
disorder.

SYMPOSIUM 10: RECENT ADVANCES IN THE GENETICS
OF POST-TRAUMATIC STRESS DISORDERS (PTSD):
GOING BEYOND GENETIC ASSOCIATIONS
S10.1 FKBP5, EARLY TRAUMA AND POST TRAUMATIC
STRESS DISORDER
E. Binder*(1,2)
1. Max-Planck Institute of Psychiatry 2. Emory University School of
Medicine, Dept. of Psychiatry and Behavioral Sciences
*binder@mpipsykl.mpg.de
Introduction: Early trauma has been shown to increase the risk for a
number of psychiatric disorders, including post traumatic stress
disorder (PTSD). This environmental effect can be moderated by
genetic polymorphisms in a number of genes, including the gene
encoding FKBP5, a co-chaperone of the glucocorticoid receptor
(GR). This effect is most likely mediated by differences in the
response of the stress response system in carriers of the opposite
alleles of these polymorphisms. However, the molecular mechanism
of this gene x environment interaction has not yet been investigated.
Methodology: We assessed the effects of early trauma and FKBP5
genotype on GR-mediated FKBP5 transcription, endocrine measures
and DNA methylation in peripheral blood in two different cohorts.
This was followed by reporter gene assays to investigate allele- and
DNA methylation-specific effects in specific FKBP5 enhancer
regions containing GR response elements (GREs).
Results: We observed that early trauma disrupts the positive
feedback between GR-activation and FKBP5 transcription in an
allele-specific manner, which is paralleled by allele-specific effects
of early trauma on GR-sensitivity. DNA-methylation of specific CGs
close to functional intronic GREs was also significantly associated
with exposure to early trauma. In two independent cohorts (N = 68
and N = 93) we observed an FKBP5 genotype x early trauma
interaction on FKBP5 DNA methylation. In addition, these specific
methylation patterns predicted ex-vivo GR sensitivity as well as the
cortisol response to a psychological stressor (Trier Social Stress
Test). The functionality of these methylation changes was confirmed
in reported gene assays.
Conclusions: The presented data suggest that the interaction of
specific functional FKBP5 polymorphisms and early trauma on adult
PTSD symptoms could be mediated by allele-specific effects of early
trauma on DNA methylation in critical enhancer regions of this gene.
35
S10.2 CORTICOTROPHIN-RELEASING HORMONE TYPE 1
RECEPTOR GENE (CRHR1) VARIANTS PREDICT POST-
TRAUMATIC STRESS DISORDER ONSET AND COURSE IN
PEDIATRIC INJURY PATIENTS
K. Koenen*
Columbia Mailman School of Public Health
*kck5@columbia.edu
Introduction: Posttraumatic stress disorder (PTSD) is a common and
disabling anxiety disorder that may occur in the aftermath of
exposure to potentially traumatic life events. PTSD is moderately
heritable, but few specific molecular variants accounting for this
heritability have been identified. Genes regulating the hypothalamicpituitary-adrenal
(HPA) axis, such as corticotrophin-releasing
hormone type 1 receptor gene (CRHR1), have been implicated in
traumatic-stress related phenotypes but have yet to be studied in
relation to PTSD.
Methodology: The present study sought to examine the relation
between 9 single nucleotide polymorphisms (SNPs) in the CRHR1
gene and posttraumatic stress symptoms in a prospective study of
pediatric injury patients (n=103) who were first assessed in the acute
aftermath of their injury at the hospital.
Results: Results indicated that multiple SNPs were associated with
acute symptoms at a univariate level, and after correction for multiple
testing, rs12944712 was significantly related to acute PTSD
symptoms. Longitudinal latent growth curve analyses suggest that
rs12944712 is also related to both acute symptom level and trajectory
of symptoms over time.
Conclusions: The present study adds support for the role of CRHR1
in the stress response following potentially traumatic event exposure
in youth.

S10.3 EVIDENCE FOR ASSOCIATION OF THE
PACAP/PAC1 RECEPTOR PATHWAY WITH POST-
TRAUMATIC STRESS SYMPTOMS
K. Ressler*(1,2), K. Mercer(1,2), B. Bradley(1,3), T. Jovanovic(1),
E. Binder(1,4), A. Myers(5), V. May(6)
1. Emory University 2. HHMI 3. VA Medical Center 4. Max Planck
Institute of Psychiatry 5. University of Miami 6. University of
Vermont
*kressle@emory.edu
Introduction: Post traumatic stress disorder is a prevalent and
debilitating psychiatric disorder. Although a number of studies have
examined genes within stress response pathways, none have yet
examined the role of the PACAP/PAC1 receptor pathway with
Posttraumatic Stress symptoms. Pituitary adenylate cyclaseactivating
polypeptide (PACAP) is known to broadly regulate the
cellular stress response. In contrast, it is unclear if the PACAP-PAC1
receptor pathway has a role in human psychological stress responses,
such as post-traumatic stress disorder (PTSD).
Methodology: We use a combination of convergent genomic
approaches, gene association studies in an all-traumatized population,
and convergent biological studies examining the association of
PACAP levels and PAC1 genotypes with PTSD symptoms and fearrelated
physiology. We then examine effects of PAC1 genotypes on
PAC1 gene expression levels, and effects of methylation at the PAC1
locus on PTSD symptoms. Finally, we examine differential
expression of the PAC1 / PACAP genes within the rodent brain
following fear conditioning and as a function of estrogen.
Results: Here we find, in heavily traumatized African American
subjects, a sex-specific association of PACAP blood levels with fear
physiology, PTSD diagnosis and symptoms in females. We examined
44 single nucleotide polymorphisms (SNPs) spanning the PACAP
(encoded by ADCYAP1) and PAC1 (encoded by ADCYAP1R1)
genes, demonstrating a sex-specific association with PTSD
(N>1200). A single SNP in a putative estrogen response element
(ERE) within ADCYAP1R1, rs2267735, predicts PTSD diagnosis and
symptoms in females only. This SNP also associates with fear
discrimination and with ADCYAP1R1 messenger RNA expression in
human brain. Methylation of ADCYAP1R1 in peripheral blood is also
associated with PTSD. Complementing these human data,
ADCYAP1R1
Conclusions: These data suggest that perturbations in the PACAP-
PAC1 pathway are involved in abnormal stress responses underlying
PTSD. These sex-specific effects may occur via estrogen regulation
of ADCYAP1R1 gene expression. PACAP levels and ADCYAP1R1
SNPs may serve as useful biomarkers to further our mechanistic
understanding of PTSD.
36
S10.4 A GENETIC VARIANT BDNF POLYMORPHISM
ALTERS EXTINCTION LEARNING IN BOTH MOUSE AND
HUMAN
F. Soliman, S. Pattwell, C. Glatt, B. Casey, F. Lee*
Weill Cornell Medical College
*fslee@med.cornell.edu
Introduction: Highly conserved neural circuitry between rodents and
humans has allowed for in-depth characterization of behavioral and
molecular processes associated with emotional learning and memory.
In this study we focused on identifying biologically valid fear-related
phenotypes across species.
Methodology: We focussed on a common single-nucleotide
polymorphism (SNP) in the brain-derived neurotrophic factor
(BDNF) gene that leads to a valine (Val) to methionine (Met)
substitution at codon 66 (Val66Met) in both mouse and human
behavioral studies as well human functional imaging studies.
Results: In an inbred genetic knock-in mouse strain that expresses
the variant BDNF allele to recapitulate the specific phenotypic
properties of the human polymorphism in vivo, we found the BDNF
Val66Met genotype was associated with treatment-resistant forms of
anxiety-like behavior. An additional objective of this study was to
test if the Val66Met genotype could affect extinction learning in our
mouse model and whether such findings could be generalized to
human populations. Both mice and human carrying the Met allele
were impaired in extinguishing a conditioned fear response, which
was paralleled by atypical frontoamygdala activity in humans.
Conclusions: Thus, this variant BDNF allele may play a role in
anxiety disorders, such as post-traumatic stress disorder, showing
impaired learning of cues that signal safety versus threat and in the
efficacy of treatments that rely on extinction mechanisms, such as
exposure therapy.

SYMPOSIUM 11: GENOMICS OF SUICIDAL BEHAVIOR
AND INTERMEDIATE PHENOTYPES
S11.1 AN INTERNATIONAL GENOME-WIDE STUDY OF
SUICIDAL BEHAVIOR AND INTERMEDIATE
PHENOTYPES IN MOOD DISORDERS
J. Mann*(1), D. Rujescu(2), G. Turecki(3), H. Galfalvy(1), C.
Hodgkinson(4), D. Goldman(4), M. Oquendo(1), Y. Huang(1), A.
Burke(1), D. Currier(1)
1. Columbia University 2. Ludwig Maximilians University 3. McGill
University 4. NIAAA
*jjm@columbia.edu
Introduction: The diathesis for suicidal behavior is partly heritable
with estimates from twin studies apporaching 50% for suicide.
Adoption studies also support a genetic component for suicide.What
is not known are the responsible genes. Most studies have been
guidied by the known neurobiolgy and ahve concentrated on genes
associated with the serotonergic system. This NIMH funded study
sought to find genes using a sample of almost 2800 cases and
controls. The phenotype was suicide or nonfatal suicide attempts.
Methodology: About 2800 cases and controls, all Caucasians,
including suicides, nonfatal suicides, most with a major depressive
disorder, and controls of two types: one psychiatric ocntrol group
with a major depressive disorder and one group of healthy volunteers
found to be free from axis I psychiatric diagnosis. Diagnoses were
done by a SCID I structured clinical interview. Genotyping was done
using the Infinium HumanHap550 Genotyping BeadChip that
contains >555,000 SNP loci with high-density tag SNP content .
Results: The sample is made up of apporximately 590 suicides and
158 sudden death controls, over 2000 nonfatal suicide attempters
with a major depressive disorder (MDD) and controls that include
healthy volunteers and 579 psychiatric controls (MDD with no life
time suicide attempt). The basic analysis compares 596 suicides and
427 nonfatal attempters to 1740 nonattempters. Next we will check
for the effects of major depression by comparing 596 suicide and 423
nonfatal attempts with major depression to 579 depressed controls.
Finally we will explore differences between suicides and nonfatal
attempters.
Conclusions: This study will generate new findings from the largest
such GWAS reported todate on suicidal behavior in major
depression.
37
S11.2 GENOME-WIDE ASSOCIATION STUDIES OF
INTERMEDIATE PHENOTYPES OF SUICIDAL BEHAVIOR:
FOCUS ON AGGRESSION AND IMPULSIVITY
D. Rujescu*
University of Munich
*dan.rujescu@med.uni-muenchen.de
Introduction: Every year over 1 million people commit and over 10
million people attempt suicide. This is one suicide every 40 seconds
and one suicide attempt every 3 seconds worldwide. Suicide accounts
for almost 2% of the world's death and it has emerged as one of the
leading causes of death among individuals aged 15-34 years in most
of the countries. The risk of suicide-related behavior is supposed to
be determined by a complex interplay of sociocultural factors,
psychiatric history, personality traits, and genetic vulnerability. This
view is supported by adoption and family studies indicating that
suicidal acts have a genetic contribution of ca. 55% that is
independent of the heritability of Axis I and II psychopathology.
Beside all other risk factors, especially personality seems to have a
high impact on suicidal behaviour.
Methodology: Aggression has been associated with suicidal
behaviour alt least since the early findings by Asberg et al. (1976).
Since then a high amount of studies could replicate this link.
Results: For that reasons we have initiated a large scale case control
genetic association study and investigated especially the role of
personality traits like aggression, anger or impulsivity as intermediate
phenotypes of suicidal behaviour.
Conclusions: We performed genome-wide association studies on
these traits in over 4000 patients and controls and will discuss these
results in relation to suicidal behaviour.

S11.3 META-ANALYSIS OF GENOME-WIDE
ASSOCIATION STUDIES OF SUICIDE ATTEMPT IN MOOD
DISORDER
R. Perlis*
Massachusetts General Hospital
*rperlis@partners.org
Introduction: Risk for suicide attempt appears to be in part heritable.
Other neuropsychiatric studies suggest that large sample sizes may be
required to detect association with common variation, and that such
studies are facilitated by meta-analysis.
Methodology: Fixed and random-effects meta-analysis was used to
investigate genome-wide association data from multiple mood
disorder cohorts. In addition, aggregate risk scores and pathwaybased
tests were used to investigate association across cohorts.
Results: No single locus reached a threshold for genomewide
significant. However, polygenic and pathway-based tests suggest
some consistency in liability across cohorts.
Conclusions: Individual loci of large effect do not appear to
contribute to inherited liability for suicide attempt among mood
disorder patients. However, tests which aggregate risk across loci
suggest the utility of alternative methodologies for follow-up of
GWAS results.
38
S11.4 GENOME-WIDE EPIGENETIC REGULATION BY
EARLY-LIFE TRAUMA AND SUICIDE
B. Labonte, M. Suderman, G. Maussion, M. Szyf, M. Meaney,
G. Turecki*
McGill University
*gustavo.turecki@mcgill.ca
Introduction: Our genome adapts to the environment pressures in
part through epigenetic mechanisms. Specific DNA methylation
changes occur in animals as a response to variation in early
environment, and recent data suggest that similar processes take place
in humans who have histories of early life adversity. Here we report a
genome-wide study of promoter methylation in individuals who died
by suicide and were victims of severe abuse during childhood.
Methodology: Promoter DNA methylation levels were profiled using
meDIP followed by microarray hybridization in hippocampal tissue
from 41 French-Canadian men (25 with a history of severe childhood
abuse and 16 controls). Methylation profiles were compared to
corresponding genome-wide gene expression profiles obtained by
mRNA arrays. Methylation differences between groups were
validated on neuronal and non-neuronal DNA fractions isolated by
fluorescence-assisted cell sorting (FACS).
Results: We identified 362 differentially methylated promoters in
individuals with a history of abuse compared to controls. Among
these promoters, 248 indicated hypermethylation and 114
hypomethylation. Validation and site–specific quantification of DNA
methylation in the most significantly differentially methylated
gene promoters indicated that methylation differences were mainly
driven by the neuronal cellular fraction. Artificially
methylated constructs mimicking the methylation state in samples
from abused suicide completers showed decreased promoter
transcriptional activity associated with decreased hippocampal
expression of the most significantly differentially methylated gene.
Conclusions: Our results suggest that childhood adversity triggers
epigenetic alterations in the promoters of several genes in
hippocampal neurons increasing risk for suicide.

SYMPOSIUM 12: PHARMACOGENETICS IN PSYCHIATRIC
PRACTICE: "YES WE CAN"
S12.1 ANXIOUS DEPRESSION AND PHARMACOGENETICS
OF ANTIDEPRESSANT DRUGS
E. Binder*(1,2)
1. Emory University School of Medicine, Dept. of Psychiatry and
Behavioral Sciences 2. Max-Planck Institute of Psychiatry
*binder@mpipsykl.mpg.de
Introduction: A number of studies have shown that suffering from
anxious depression is one of the most consistent predictors for a
negative treatment outcome. This might be an indication for the fact
that anxious depression could be biologically and genetically distinct
subtype of major depression, resulting in different genetic predictors
for antidepressant treatment response.
Methodology: Genome-wide and candidate gene-base association
data from two large pharmacogenetics cohorts, the "Munich
Antidepressant Signature"-MARS project and the "Sequenced
Treatment Alternatives to Relieve Depression" - STAR*D study will
be presented. The analyses will focus on gene x anxious depression
interactions on antidepressant treatment response.
Results: In both studies, anxious depression is a strong negative
predictor of treatment outcome. Genetic polymorphisms in genes
within the stress hormone system, CRHR1 and CRHBP interact with
anxious depression to predict treatment response. In both genes, the
pharmacogenetic associations are only observed in patients with
anxious depression. Data from a genome-wide association study in
the MARS samples show that a number of polymorphisms strongly
interact with anxious depression to predict antidepressant therapy
response. These results are currently being followed up in the
STAR*D as well as GENDEP cohorts.
Conclusions: Anxious depression is an important factor to be
considered in antidepressant drug pharmacogenetic studies. Selected
genetic predictors appear to be specific for this subtype of major
depression.
39
S12.2 NTRK2 AND PDE11A PREDICT RESPONSE TO
LITHIUM IN BIPOLAR DISORDER IN PATIENTS WITH
ELATED MANIA AND POSITIVE FAMILY HISTORY
J. Kelsoe*(1,2), S. Leckband(1,2), A. DeModena(1,2), T.
Shekhtman(1,2), M. McCarthy(1,2)
1. Department of Psychiatry, University of California, San Diego 2.
Department of Psychiatry, VA San Diego Healthcare System
*jkelsoe@ucsd.edu
Introduction: Lithium was the first mood stabilizer medication for
bipolar disorder, and remains the gold standard with the strongest
evidence for efficacy and reduction of suicide risk. A subset of
patients have a very robust response with virtual elimination of
episodes. Several clinical features have been shown to predict good
response to lithium, in particular, elated mania and family history of
bipolar disorder, and it has been proposed that bipolar disorder with
good lithium response may comprise a biologically distinct form of
illness. As some data suggest that this excellent lithium response is
best obtained when treatment begins soon after onset of illness, there
is a great clinical need for methods to predict response.
Methodology: We have retrospectively assessed lithium response in
a set of 288 bipolar patients using information from SCID or DIGS
interview, lifechart and medical records. 632 SNPs were genotyped
in 50 genes selected for their putative role in lithium’s mechanism of
action or bipolar disorder susceptibility. Positive SNPs from this
analysis were examined in an independent prospective clinical trial
sample of 77 subjects employing a monotherapy relapse prevention
design with two year followup.
Results: In the retrospective sample, SNPs in several genes showed
nominal significant evidence of association to response. This
evidence was substantially stronger in patients with a positive family
history of bipolar disorder and a history of elated mania and in
particular implicated NTRK2 (p=0.006) and PDE11A (p=0.0004).
Association of NTRK2 was replicated in the independent prospective
sample (rs1387923, p=0.028).
Conclusions: To extend these studies in a larger sample, we have
recently begun the Pharmacogenomics of Bipolar Disorder (PGBD)
study which will use a similar prospective relapse prevention design
at 10 international collaborative sites. Together these data support the
idea that lithium responsive bipolar disorder may be genetically and
clinically distinct, and that incorporating clinical covariates
considerably improves the power to detect associated genes.

S12.3 CLINICAL INTERPRETATION OF WHOLE EXOME
SEQUENCING DATA IN ANTIDEPRESSANT TREATMENT
RESPONSE
G. Laje*, N. Akula, F. McMahon
NIMH
*lajeg@mail.nih.gov
Introduction: A wide range of markers associated with
antidepressant response have been detected through candidate gene,
genome-wide and meta-analyses. However, these common genetic
variants have small effect and no current clinical utility. It is possible
that rare variants that may offer additional insight into the
pathophysiology of this complex phenotype. We undertook a whole
exome sequencing experiment to search for uncommon and rare
variants in individuals selected from the Sequenced Treatment
Alternatives to Relieve Depression study (STAR*D).
Methodology: We selected 8 individuals with Caucasian Europeanancestry
from the STAR*D sample (n =8) who represented
treatment-resistant cases (extreme non-responders) and sustained
treatment remitters. Extreme non-responders (NR), derived from
Level 4, had failed 4 treatment strategies. Sustained remitters (SR)
were matched on gender, anxious depression status, treatment
adherence, and ancestry. Additionally, the controls, were remitters at
Level 1 endpoint and did not relapse in the 6 months post Level 1
completion (QIDS-SR 11). All samples were sequenced at EdgeBio
using a SOLiD platform with ≥ 10X coverage.
Results: Initial results pertaining to single nucleotide variants
(SNVs) revealed that each participant had about 90,000 SNVs on
initial annotation. To characterize the potential impact of the SNVs
on the resulting protein, we used SIFT (Sorting Intolerant From
Tolerant), an algorithm that predicts whether an amino acid
substitution affects function, in both novel and known variants. There
were no differences in the mean number of known variant s between
groups. However, the mean number of novel variants, predicted as
damaging, had a small but significant difference in non responders
(89.8+/-7.2) and sustained remitters (100.8+/-3.8) (p 0.05).
Conclusions: The detection of rare variants through high throughput
sequencing may point to relevant genes involved in the
pathophysiology of treatment-resistant depression.
40
S12.4 GENETICS OF ANTIPSYCHOTIC DRUG RESPONSE
AND INDUCED WEIGHT GAIN
D. Müller*(1), A. Tiwari(1), N. Chowdhury(1), T. Lett(1), E.
Brandl(1), O. Likhodi(1), N. Freeman(1), J. Lieberman(2), S.
Potkin(3), H. Meltzer(4), J. Kennedy(1)
1. Dept. of Psychiatry, University of Toronto at CAMH 2. Columbia
University 3. Department of Psychiatry and Human Behavior,
University of California 4. Vanderbilt University
*daniel_mueller@camh.net
Introduction: The substantial inter-individual variability observed in
response and side effects with antipsychotic drugs is likely to largely
depend on genetic factors. Based on findings from our group pointing
to an association between a putative functional SNP in the 3’UTR of
the neurexin-1 (NRXN1) gene and MRI white matter volume in
frontal brain regions, we tested for an association between the
NRXN1 gene and response to antipsychotic drugs.
One of the most debilitating side effects, emerging with many newer
antipsychotic drugs, is substantial weight gain associated with
cardiovascular complications and metabolic syndrome. Since
previous findings by our group and collaborators strongly implicated
the leptin-melanocortin energy homeostasis system to be associated
with antipsychotic-induced weight gain, we investigated four variants
in each of the melanocortin-4 receptor and the neuropeptide Y (NPY)
genes in our ongoing studies.
Methodology: A total of 237 patients who underwent treatment for
chronic schizophrenia or schizoaffective disorder were evaluated for
antipsychotic response and induced weight gain for up to six months.
We genotyped one SNP in the NRXN1 gene (rs1045881) for
response to clozapine treatment in European-Americans (n = 169).
For the weight gain phenotype, SNPs rs2229616, rs17782313,
rs11872992, rs8087522 were tested in the MC4R gene while SNPs
rs16147, rs16475, rs5573 and rs5574 were tested in the NPY gene.
Results: The neurexin rs1045881 T-allele was over represented in
the non-responder group, suggesting the variant may influence
clozapine response (OR = 2.2; p = 0.01). As for the phenotype of
antipsychotic-induced weight gain and the MC4R gene, analysis
showed that clozapine treated patients of European ancestry who
were carriers of the rs8087522 A-allele (AG+AA) on average gained
significantly more weight than non-carriers (p=0.027). Furthermore,
a functional relevance of this SNP was revealed by electrophoretic
mobility shift assay analyses, where the presence of the A-allele
appears to create a transcription factor-binding site. With respect to
the NPY gene, a significant association of rs16147 genotype with
weight change was observed in clozapine treated patients of
European descent (p=.002). Our preliminary analyses revealed that
carriers of the functionally relevant C-allele gained significantly more
weight compared to individuals with TT-genotype (TC+CC vs. TT;
5.61%±5.4% vs. 0.32%±4.8%). Similarly, two other polymorphisms
(rs5573 and rs5574) were significantly associated with weight change
(p=.009 and p=.022), although these three associated polymorphisms
were found to be in high linkage disequilibrium.
Conclusions: Our results tentatively suggest novel associations
between functionally relevant markers with response (NRXN1) and
induced weight gain (MC4R and NPY) in patients treated with
antipsychotic medication for schizophrenia. However, replication and
further work is needed before screening of these genes will provide
more efficient treatment strategies through personalized medicine
algorithms.

INDIVIDUAL ORAL
PRESENTATIONS
41

ORAL PRESENTATIONS SESSION 1: FUNCTIONAL
GENOMICS & MODEL ORGANISMS I
OPS1.1 INVESTIGATING THE ROLE OF MUTATIONS IN
ZFP804A ON GENE EXPRESSION
D. Knight*, L. Jones, L. Wilkinson, T. Al-Janabi, M. Owen, D.
Blake, M. O'Donovan
Cardiff University
*knightdj2@cf.ac.uk
Introduction: Genome-wide significant evidence for association
between a polymorphism in the gene and schizophrenia followed by
replication has identified ZNF804A as one of a few strongly
implicated schizophrenia susceptibility genes. Determining the
function of the ZNF804A protein, which is currently unknown, may
provide a way of elucidating the pathophysiology of this common,
complex disorder. Based on sequence homology ZNF804A is
hypothesised to regulate gene expression. The main focus of this
work was to identify in the brain tissues of mice in which the
orthologue Zfp804a has been mutated to carry a nonsense variant,
genes that exhibit altered expression using global assays of gene
expression.
Methodology: Using the Genechip Mouse Exon 1.0 ST Array
(Affymetrix) and brain tissue from 9 wild type (WT) control mice
and 7 mice homozygous for the mutation in Zfp804a global gene
expression was investigated. Partek Genomics suite 6.5 (Partek Inc,
St Louis, MO) was used for data pre-processing and expression
analysis. In addition the mouse orthologues of genome wide
significant genes from the PGC SZ GWAS were specifically
investigated for differential expression.
Results: Following a Bonferroni correction transcripts of 29 genes
showed significant alterations in expression. After FDR correction,
we identified no pathways that were significantly enriched for genes
with nominally significantly (p

OPS1.3 ESTABLISHMENT OF COCAINE PREFERENCE IS
DELAYED IN αCAMKII AUTOPHOSPHORYLATION-
DEFICIENT MICE
ECIP
A. Easton*(1), W. Lucchesi(2), G. Schumann(1), C. Fernandes(3),
K. Giese(2), C. Muller(1,4)
1. Kings College London, MRC Social, Genetic and Developmental
Psychiatry Centre 2. Kings College London, JBC MRC Centre for
Neurodegeneration Research 3. Kings College London, Dept of
Psychosis Studies 4. Univ of Erlangen, Dept of Psychiatry and
Psychotherapy
*alanna.c.easton@kcl.ac.uk
Introduction: Cocaine dependence has been classified by DSM-IV
as a psychiatric disorder. Cocaine is the most widely used illicit
psycho-stimulant drug in the UK with an estimated 1,000,000 users,
and a prevalence rate of lifetime use between 3 % and 5% (UNODC
2009). Despite this, the underlying processes by which cocaine
dependence is established are not known but believed to involve
molecular mechanisms of learning and memory. Alpha
calcium/calmodulin dependent protein kinase II (αCaMKII) is a
major synaptic kinase that is critical for memory formation. Upon
autophosphorylation, αCaMKII switches to an autonomous state of
activity after calcium levels drop, preserving kinase activity. It has
been reported that αCaMKII autophosphorylation-deficient mice (Mt)
show severe one-trial learning impairments compared to
heterozygous (Ht) and wild type (WT) counterparts. However, the
requirement for the aCaMKII autophosphorylation can be overcome
by repeated training. Accordingly, we hypothesised that the
behavioural and motivational properties associated with drugs of
addiction will initially be attenuated in the Mt mice, diminishing after
repeated treatment.
Methodology: We tested cocaine’s effects on the learning curve
established in a conditioned place preference (CPP) paradigm.
Results: Mt mice were impaired in learning cocaine CPP, but after a
7 day period with no treatment or conditioning (‘incubation’), Mt
mice had the same level of preference as Ht and WT mice. Acute
locomotor responses to cocaine and saline were identical in all
groups. We can therefore rule out to a great extent metabolism
differences in these mice. There was a significant conditioned
hyperlocomotion effect seen in all genotypes with cocaine, but not
saline. This suggests that the aCaMKII autophosphorylation is not
required for this type of learning. Cocaine, produced considerable
behavioural stimulating effects in all genotypes, but this sensitised
over 7 treatments. Thus, this sensitisation is another type of learning
that does not require aCaMKII autophosphorylation. Taken together,
this study supports the role of learning processes in the development
of addictive behaviours.
Conclusions: Data suggest an important, specific role for αCaMKII
autophosphorylation in the establishment of addiction related
behavioural responses.
43
OPS1.4 LENTIVIRAL MEDIATED-MEDIATED GENE
DELIVERY REVEALS DISTINCT ROLES OF NUCLEUS
ACCUMBENS DOPAMINE D2 AND D3 RECEPTORS IN
NOVELTY- AND LIGHT-INDUCED LOCOMOTOR
ACTIVITY
ECIP
A. Fernandes*(1), A. Easton(1), M. De Souza Silva(2), G.
Schumann(1), C. Müller(1,3), S. Desrivières(1)
1. 1MRC-SGDP-Centre, Institute of Psychiatry, King's College
London 2. Centre for Behavioural Neuroscience and Centre for
Biological and Medical Research, University of Düsseldorf,
Universitätsstr. 1, 40225 3. Section of Addiction Medicine,
Psychiatric University Hospital, Friedrich-Alexander-University
Erlangen-Nuremberg, Schwabachanlage 6,
*alinda.fernandes@kcl.ac.uk
Introduction: The importance of dopamine in brain function is
shown by many functional studies investigating effects of alteration
of the dopaminergic system leads to changes in cognitive and motor
functions. Although the roles of specific dopamine receptors in
behaviour have been extensively investigated using pharmacological
agents and knockout mice, non-specificity of ligands and
compensatory molecular adaptations in mutated animals restrict the
interpretation of the results.
Methodology: To explore the role of the dopamine D2 and D3
receptors (D2R and D3R) in rats, we used lentivirus-mediated gene
knockdown and overexpression to specifically manipulate expression
levels of these genes in the rat nucleus accumbens (NAcc), a brain
area important for motor response and motivation. Lentiviruses,
inducing expression of rat D2R or D3R, or efficient knockdown of
either receptor by small hairpin (sh)RNAs knockdown were
stereotaxically injected into the NAcc. Novelty- and light-induced
locomotor activities as well as anxiety-related behaviours were
measured.
Results: In the present study we aimed at investigating the specific
contributions of D2R and D3R, expressed in the NAcc, in novelty-
and light-induced locomotor activity. Using lentiviral-mediated overexpression
and gene knockdown to specifically and locally overexpress
or repress these genes. We found that NAcc D2R and D3R
share a similar function in spontaneous locomotor activity, thus
regulating activity in a new environment, but not in a familiar
environment. However, there was a dissociation of in the role of
NAcc D2R and D3R in visual stimulation-induced locomotor
activity. While NAcc dopamine D2 receptors limited light-induced
activity, the behaviour was facilitated by NAcc dopamine D3
receptors. These findings are unlikely to reflect altered anxiety levels
as no clear differences between groups were observed in wellestablished
animal models of anxiety.
Conclusions: In conclusion, this study demonstrates that lentivirus
mediated gene delivery to a distinct region in the brain can provide
insights into the brain region specific functionality of genes in
behaviour. Our results suggest NAcc D2R and D3R are required for
spontaneous locomotor activity in a new environment, but not in a
familiar environment. There was little evidence for both receptors in
anxiety-related behaviours. However, we were able to clearly
distinguish opposite roles of Nac D2R and D3R in visual stimulationinduced
locomotor activity.

OPS1.5 IN VIVO MICRORNA CSF PROFILING IN
PATIENTS WITH SCHIZOPHRENIA
ECIP
J. Gallego*(1), T. Lencz(1, 2, 3, 4), M. Gordon(1, 2, 3, 4), J.
Gentile(1), S. Ventura(1), C. Morell(1), N. Chitkara(1), A.
Malhotra(1, 2, 3, 4)
1. The Zucker Hillside Hospital 2. The Feinstein Institute for Medical
Research 3. Albert Einstein College of Medicine 4. Hofstra North
Shore-LIJ school of medicine
*jgallego@nshs.edu
Introduction: MicroRNAs are small non-coding RNA molecules
that are involved in post-transcriptional regulation of messenger
RNAs. Recent studies have started to link alterations in miRNA
expression to schizophrenia and other psychiatric disorders.
However, most of these studies have examined a small number of
microRNAs and/or have used post-mortem brain tissue or whole
blood as the source of transcript. By contrast, examination of a broad
array of microRNAs in cerebrospinal fluid might provide an in vivo
biomarker more directly reflecting functional changes in the brain.
However, to our knowledge, no study has been conducted
investigating the presence of microRNAs in CSF in schizophrenia or
any other psychiatric disorder.
Methodology: Four patients with chronic schizophrenia and four
healthy volunteers underwent lumbar puncture and a standard blood
draw. For each subject, total RNA was separately extracted from 3-
5ml of CSF and one PaxGene tube of blood. Expression of 381
validated microRNAs was assessed from each biofluid type for each
of the subjects with the Taqman Human MicroRNA A array (Applied
Biosystems), which uses real-time RT-PCR to quantify the number of
amplification cycles (Ct) required to reach a given threshold.
Results: A mean of 136.5 (SD=11) miRNAs were obtained from
CSF in healthy volunteers (male: 100%, mean age: 38.8, black: 75%)
and a mean of 180.5 (SD=11.2) miRNAs were obtained in patients
with schizophrenia (male: 100%, mean age: 41, black: 75%).
Approximately one-third of all CSF-expressed microRNAs
demonstrated robust levels of expression (Ct

OPS2.2 GENOME WIDE STUDIES OF IMPRINTED GENES
IN THE FRONTAL CORTEX: TRANSCRIPTOME AND
METHYLOME ANALYSIS
C. Barr*(1,2), W. Xie(3), K. Wigg(1), E. Dempster(1), C.
Barbacioru(4), Y. Feng(1), L. Gomez(1), P. Monnier(1), R. Logan(1),
J. Eubanks(1), B. Ren(3)
1. The Toronto Western Research Institute 2. The Hospital for Sick
Children 3. Ludwig Institute for Cancer Research 4. Life
Technologies
*cbarr@uhnres.utoronto.ca
Introduction: Current data support approximately 90 validated
imprinted genes in mice, but recent estimates indicate that this
number may be well over 1,000. Many of the genes are imprinted in
a tissue/cell type specific pattern and little is known of these
genes. Previous evidence indicates that imprinted genes influence the
development of specific brain regions and we sought to identify
imprinted genes contributing to the development of the frontal cortex
using crosses and reverse crosses of mouse strains to determine the
parent-of-origin of expressed genes.
Methodology: We used next generation sequencing of RNA (RNAseq),
chromatin immunoprecipitation to histone modifications (ChiPseq),
and bisulfite sequencing (MethylC-Seq) of DNA from the
frontal cortex of the adult F1 mice to identity transcripts and
epigenetic marks with parent-of-origin effects.
Results: Using a FDR of .01, and requiring that the same parent-oforigin
bias was evident in 3 biological replicates, we identified
known imprinted genes as well as novel patterns of expression for
known imprinted genes. We also identified 109 novel transcripts
with parent-of-origin effects. Using Methyl-seq we correctly
identified 27 of 29 known differentially methylated regions (DMRs)
associated with known imprinted genes as well as novel DMRs, most
within known imprinted regions. However none of the novel
imprinted transcripts that we identified using RNA-seq or were
identified in a recent study, were marked by a DMR or by chromatin
patterns that were indicative of imprinting.
Conclusions: The finding of novel imprinted genes indicates that the
number of imprinted genes with tissue specific effects is
underestimated and requires further studies to identify the full
complement of imprinted genes in brain. However the failure to find
epigenetic patterns supporting these genes indicates either that these
are false positive findings or an unknown mechanism confers the
imprint. The understanding of parent-of-origin effects in specific
brain regions will make a significant contribution to our
understanding of the role of imprinting in brain function and behavior
and the use of high throughput technologies now allows for the
comprehensive study of mechanisms regulating imprinting.
45
OPS2.3 ANTIDEPRESSANT TREATMENT IS ASSOCIATED
WITH EPIGENETIC ALTERATIONS IN THE PROMOTER
OF P11 IN A GENETIC MODEL OF DEPRESSION
ECIP
P. Melas*(1), M. Rogdaki(1), A. Lennartsson(1), K. Björk(1), H.
Qi(1), A. Witasp(1), M. Werme(1), G. Wegener(2), A. Mathé(1), P.
Svenningsson(1), C. Lavebratt(1)
1. Karolinska Institute 2. Aarhus University Hospital
*philippe.melas@ki.se
Introduction: P11 (S100A10) has been associated with the
pathophysiology of depression both in humans and rodent models.
Different types of antidepressants have been shown to increase P11
levels in distinct brain regions and P11 gene therapy was recently
proven effective in reversing depressive-like behaviors in mice.
However, the molecular mechanisms that govern P11 gene
expression in response to antidepressants still remain elusive.
Methodology: Prefrontal cortical regions of a genetic rodent model
of depression were examined. P11 mRNA and protein levels were
measured by in situ hybridization, RT-PCR and Western blotting.
P11 exons and the proximal promoter region of the gene were
sequenced. Pyrosequencing technology was used to quantify the
DNA methylation levels at the promoter region. Global DNA
methylation levels were examined using the LUMA assay.
Quantitative RT-PCR was used to investigate the mRNA levels of
three DNA methyltransferases (Dnmt1, Dnmt3a and Dnmt3b) and
four candidate DNA demethylases (Mbd2, Mbd4, Aid and Gadd45b).
Results: In this study we report decreased levels of P11, associated
with higher DNA methylation in the promoter region, in the
prefrontal cortex of the FSL (Flinders Sensitive Line) genetic rodent
model of depression. This hypermethylated pattern was reversed to
normal, as indicated by the control line, after chronic administration
of escitalopram (a selective serotonin reuptake inhibitor SSRI). The
escitalopram-induced hypomethylation was associated with both an
increase in P11 gene expression and a reduction in the mRNA levels
of two DNA methyltransferases that have been shown to maintain
DNA methylation in adult forebrain neurons (Dnmt1 andDnmt3a).
Conclusions: In conclusion, our data further support a role for P11 in
depression-like states and suggest that this gene is controlled by
epigenetic mechanisms that can be affected by antidepressant
treatment.

OPS2.4 THE SLC6A4 VNTR GENOTYPE DETERMINES
TRANSCRIPTION FACTOR BINDING AND EPIGENETIC
VARIATION OF THIS GENE IN RESPONSE TO COCAINE
IN VITRO
J. Quinn*, V. Bubb, K. Haddley, P. Myers
University of Liverpool
*jquinn@liv.ac.uk
Introduction: We have previously demonstrated that the variable
number tandem repeats (VNTRs) termed LPR and Stin2 within the
promoter and intron 2 of the serotonin transporter (SLC6A4) gene
respectively, act as differential transcriptional regulators in reporter
gene constructs both in vivo and in vitro. SLC6A4 regulation is in
part regulated by the transcription factor CTCF via the Stin2
domain. We now explore whether CTCF can also modify the
transcriptional properties of the LPR. We demonstrate that CTCF
will regulate an LPR directed reporter gene in JAr cells and that
CTCF will bind to the endogenous LPR region. The binding of CTCF
to the LPR is sensitive to challenge and the genotype determines
CTCF binding and epigenetic variation at the locus in response to
cocaine in vitro. Interestingly the loss of CTCF binding at the LPR in
response to cocaine is correlated with the binding of the methylated
DNA binding protein MeCP2 at the LPR. No variation of CTCF
binding was observed at the Stin2 VNTR in this model although we
had previously noted differential binding of CTCF to this VNTR in
response to Lithium.
Methodology: We measure the ability of the LPR and Stin2 VNTRs
to support marker gene expression in JAr cells in response to cocaine
and over expression of CTCF from an expression construct.We have
used antibodies against CTCF, MeCP2 and various histone marks to
address binding of these factors of the endogenous SLC6A4 VNTRs
and its promoter in ChIP analysis.
Results: Biochemically and functionally the LPR and Stin2 VNTRs
were differentially regulated by the transcription factor CTCF. ChIP
analysis allowed us to demonstrate differential CTCF binding to the
LPR in response to cocaine. Prior to cocaine exposure both alleles of
the LPR bound CTCF, however CTCF only bound to the long allele
following exposure. Significantly, this differential effect of cocaine
on binding of CTCF was correlated with the binding of the
transcriptional regulator MeCP2 specifically to the short allele and
recruiting the histone deacetylase complex (HDAC). Concurrently,
cocaine increased the association of positive histone marks over the
SLC6A4 gene locus.
Conclusions: The data demonstrated that exposure of JAr cells to
cocaine can result in differential binding of CTCF, MeCP2 and
HDAC to the LPR VNTR based on its specific genotype. This was
correlated with modulation of histone marks that might alter
epigenetic parameters affecting gene expression after the initial
challenge. CTCF and MeCP2 are well characterised major
modulators of epigenetic parameters and often converge on similar
genes to modulate imprinting parameters. This could be a
mechanism by which the genotype of SLC6A4 alters the expression
of the gene in the medium to long term after challenge. Related
VNTR domains populate the genome and can be both conserved in
evolution and rapidly evolving. Extrapolation of our data on the
SLC6A4 VNTRs suggests that such polymorphic VNTRs are
potentially a major modulator of gene expression and therefore
targets to mediate differential gene expression associated with
psychiatric disorders.
46
OPS2.5 NEXT-GENERATION SEQUENCING IDENTIFIES
MIRNAS ASSOCIATED WITH MOOD DISORDERS
M. Carless*(1), J. Neary(1), M. Zlojutro(1), T. Dyer(1), J. Curran(1),
L. Almasy(1), R. Duggirala(1), D. Glahn(2,3), J. Blangero(1)
1. Texas Biomedical Research Institute, Department of Genetics 2.
Yale University, Department of Psychiatry 3. Olin Psychiatric
Research Center, Institute of Living
*mcarless@sfbrgenetics.org
Introduction: miRNAs are potent regulators of gene expression that
have recently been shown to be targets for the regulation of mood
stabilizers. Although several miRNAs are suggested targets of mood
stabilizers, their expression in individuals suffering from mood
disorders and their biological role in related neuroanatomical and
neurocognitive phenotypes are not well studied.
Methodology: We have collected samples from approximately 1,300
individuals within ~40 families that are part of the Genetics of Brain
Structure and Function (GOBSF) study for which we have extensive
neuroanatomical and neurocognitive data as well as measures of
depression, anxiety and substance abuse. In addition, we have
collected samples from ~100 individuals (siblings) that are part of the
Genetics of Bipolar Disorder (GOBD) study for which we have
identical neuroanatomical and neurocognitive measures, as well as
additional neuropsychological data. Using the newly-released TruSeq
platform by Illumina, we have used multiplex-based sequencing
analysis to identify miRNAs associated with depression in a subset
(n=60) of the GOBSF population.
Results: Several miRNAs were found to be associated with major
depressive disorder (MDD), recurrent MDD (rMDD) and the Beck
Depression Inventory (BDI) at a nominal p-value of 0.05. hsa-let-7e
(p=0.045; p=0.024; p=0.029), hsa-miR-29c* (p=0.0.025; p=0.024;
p=0.036) and hsa-miR-378* (p=0.006; p=0.021; p=0.031) were
associated with all three measures of depression (MDD, rMDD and
BDI, respectively). In addition, we identified associations with
several miRNAs for which there is evidence of decreased expression
in bipolar disorder (MDD: hsa-miR-22, p=0.021/BDI: hsa-miR-15a,
p=0.036; hsa-miR-190, p=0.006; hsa-miR-27b, p=0.024) or which
are suggested targets of mood stabilizers (rMDD: hsa-miR-30c,
p=0.010; hsa-let-7b, p=0.015/BDI: hsa-miR-155, p=0.006; hsa-miR-
34a, p=0.038; hsa-let-7b, p=0.026). Although no associations were
seen that met correction for multiple testing, we believe that the
consistency seen across multiple measures of depression, as well as
prior evidence for a role in mood disorders, suggests that the
miRNAs identified in this preliminary analysis may indeed play a
role in depression and that analysis with our larger cohort will yield
more powerful results.
Conclusions: We are continuing to analyze sequencing data in the
remaining GOBSF samples, as well as in our GOBD cohort to
identify stronger associations of miRNAs with depression and bipolar
disorder and also to gain sufficient power to detect associations with
neuroanatomical and neurocognitive phenotypes. In addition, we are
analyzing potentially novel miRNAs, of which we have identified
145 candidates to date, to determine whether they are true miRNAs
and to investigate their role in mood disorders.

ORAL PRESENTATIONS SESSION 3: PHENOTYPES &
ENDOPHENOTYPES
OPS3.1 GENOME-WIDE ASSOCIATION IMPLICATES
FGF14 IN AMYGDALA VOLUME AND FEAR PROCESSING
D. Glahn*(1,2), M. Carless(3), J. Kent(3), A. Winkler(1,2), T.
Dyer(3), J. Curran(3), M. Johnson(3), H. Göring(3), E. Moses(3), R.
Olvera(4), P. Kochunov(4), P. Fox(4), L. Almasy(3), R.
Duggirala(3), J. Blangero(3)
1. Olin Neuropsychiatric Research Center, Institute of Living 2. Yale
University 3. Texas Biomedical Research Institute 4. UT Health
Science Center, San Antonio
*david.glahn@yale.edu
Introduction: The amygdala has a preferential role in processing
emotional stimuli and fear conditioning. Amygdala dysfunction has
been documented in a number of mental illnesses, including mood
disorders, schizophrenia, anxiety disorders, post-traumatic stress
disorder and addiction. Determining the genetic factors that influence
amygdala function and structure should provide empirically defined
candidate genes for these mental illnesses.
Methodology: To that end, we genotyped more than one million
genetic variants throughout the genome of 605 Mexican American
individuals from randomly selected extended pedigrees, for which we
have extensive neuroanatomical and neurocognitive data.
Results: We undertook a genome-wide association analysis of
amygdala volume and identified a single nucleotide polymorphism
(SNP), rs1336722, which was significantly associated with amygdala
volume (p=6.7x10 -8 ). Located within intron 1 of the FGF14 gene, the
C allele (frequency=0.44) accounts for nearly 4% of the phenotypic
variation seen in amygdala volume and is associated with a decline in
volume. Three other SNPs (rs1415060, rs1336709, and rs9518703)
within intron 1 of FGF14, which were in linkage disequilibrium with
rs1336722, also showed genome wide significance. To determine if
rs1336722 influences fearful facial perception in healthy individuals,
subjects were asked to choose which of five words (e.g. happy, sad,
angry, fear, or neutral) best represents the emotion portrayed on a
series of 40 faces. While the identification of fearful facial
expressions, relative to neutral faces, was significantly influenced by
rs13366722 (p=0.002), task performance in general was not
influenced by this SNP (p=0.766).
Conclusions: FGF14codes for a fibroblast growth factor that is
expressed in the developing and adult central nervous system.
Mutations within this gene have been associated with dyskinesia,
cerebellar ataxia and mild mental retardation. Further, animal models
have suggested a function for FGF14 in neuronal signaling, axonal
trafficking and synaptosomal function and indicate that reduced
FGF14 may result in decreased response to dopamine agonists. We
have identified a novel polymorphism that is associated with
amygdala volume and are currently re-sequencing and genotyping the
FGF14 gene more comprehensively to identify potential functional
variation that may contribute to amygdala volume and the
development of mental illnesses, particularly mood disorders
47
OPS3.2 FURTHER EVIDENCE FOR GENETIC
ASSOCIATION BETWEEN SCHIZOPHRENIA AND
BIPOLAR FROM NEW IMMUNOCHIP DATA ANALYSIS
M. Hamshere*(1), E. Green(1), D. Grozeva(1), I. Jones(1), L.
Jones(2), K. Gordon-Smith (2), L. Forty(1), J. Moran(3), J. Kranz(3),
S. Purcell(3,4,5), P. Sklar(3,4,5), M. Owen(1), M. O'Donovan(1), N.
Craddock(1)
1. MRC Centre for Neuropsychiatric Genetics and Genomics, School
of Medicine, Cardiff University, Heath Park, CF14 4XN 2.
Department of Psychiatry, University of Birmingham, National
Centre for Mental Health, 25 Vincent Drive, B15 2FG 3. Stanley
Centre for Psychiatric Research, Broad Institute 4. Department of
Psychiatry, Harvard Medical School 5. Psychiatric and
Neurodevelopmental Genetics Unit, Centre for Human Genetic
research, Massachusetts General Hospital
*hamshereml@cardiff.ac.uk
Introduction: We present Illumina ImmunoChip results data for
bipolar disorder. The ImmunoChip contains fine mapping data for
genes from autoimmune disorders, including extensive SNP data in
the MHC region. Also of particular interest to bipolar is that the
genes CACNA1C (alpha 1C subunit of the L-type voltage-gated
calcium channel) and ANK3 (ankyrin G) are fine mapped. In
addition, interesting SNPs from previous studies were included on the
chip, including the top SNPs in CACNA1C and ANK3 from Ferreira
et al (2008), plus a number of key schizophrenia SNPs identified in
O’Donovan et al (2008), the MGS study (2009), the ISC study (2009)
and the Sgene study (2009).
Methodology: After extensive quality control of the data, genotypes
were available for 2,630 bipolar and 4,322 control individuals at each
of 127,124 autosomal SNPs. Each SNP was analysed with the
Cochran Armitage Trend test, and systematic inflation of all the trend
statistics was adjusted with the genomic control lambda statistic. A
subset of the sample have not been analysed previously (1,388
bipolar and 1,398 controls), allowing us to investigate independent
evidence of association from previous studies. Here we describe
results from SNPs previously associated with schizophrenia.
Results: We will discuss our experiences of analysing data on the
ImmunoChip and highlight some issues relevant to analysing nongenome-wide
chip data with regions of extensive linkage
disequilibium. Analysis of the schizophrenia defined SNPs of interest
showed greater evidence for association in bipolar disorder than
expected by chance. Loci of interest include rs17594721 (TCF4
p=0.0103 in the independent sample), rs9922369 (RPGRIP1L
p=0.0279) and rs13199775 (SLC17A1 p=0.0359).
Conclusions: Our results provide us with an interesting overview the
main candidate SNPs for schizophrenia analysed in our independent
bipolar disorder sample (i.e. not previously included in any meta
analyses). This adds to the evidence for genetic overlap between
schizophrenia and bipolar disorder.

OPS3.3 NEUREXIN-1 AND SCHIZOPHRENIA
SUBPHENOTYPES: BRAIN MORPHOLOGY AND
CLOZAPINE RESPONSE
ECIP
T. Lett*(1), A. Voineskos(1), A. Tiwari(1), J. Lerch(2), S. Ameis(2),
T. Rajji(1), B. Mulsant(1), H. Meltzer(3), J. Lieberman(4), S.
Potkin(5), D. Müller(1), J. Kennedy(1)
1. Centre for Addiction and Mental Health 2. Hospital for Sick
Children 3. Vanderbilt University 4. Columbia University 5.
University of California
*tristram_lett
Introduction: CNV structural variations in the neurexin-1 (NRXN1)
gene increase the risk for both autism spectrum disorders (ASD) and
schizophrenia. However, the effect in which NRXN1 gene variations
may be related to the important subphenotypes of brain morphology
and clozapine response has had little attention. Furthermore,
schizophrenia is hypothesized to be at least in part, a disorder related
to N-methyl D-aspartate (NMDA) receptor dysfunction.
NRXN1modulates recruitment of NMDA receptors to the presynaptic
membrane. Clozapine normalizes cortical hyperactivity of
NMDA receptors; thus, regulation of NRXN1 may mediate
clozapine’s efficacy.
Methodology: 53 healthy individuals between 18-59 years of age
received structural MRI scans, which were processed to determine
cortical gray and white matter lobar volumes, and volumes of striatal
and thalamic structures. Each subject’s sensorimotor function was
also assessed. All were genotyped at 11 single nucleotide
polymorphisms of the NRXN1 gene. The general linear model was
used to calculate the influence of NRXN1 variation on neural and
cognitive phenotypes. Next, in silico analyses were conducted to
assess potential functional relevance of any polymorphisms
associated with brain measures. Finally, in an independent sample,
rs1045881 was genotyped in 169 European-American schizophrenia
patients prospectively assessed for clozapine response. Treatment
response was defined as a 20% reduction in Brief Psychiatric Rating
Scale (BPRS) from the time of enrolment into the study (baseline) to
after 6 months of clozapine treatment.
Results: A polymorphism located in the 3’ untranslated region of
NRXN1 significantly influenced white matter volumes in whole brain
and frontal lobes after correcting for total brain volume, age and
multiple comparisons (F2.25=5.498, p = 0.004; F1,49=8.231, p=0.006,
respectively). Follow-up in silico analyses revealed that rs1045881 is
a putative microRNA binding site that may regulate NRXN1
expression. This variant also influenced sensorimotor performance, a
neurocognitive function impaired in schizophrenia patients. We
observed an association with clozapine response (20% reduction in
BPRS scores; genotypic:p = 0.03, OR= 2.2 [1.08-4.30]). Post hoc
analysis of quantitative assessment of positive and negative
symptoms scores revealed a significant association between BPRS
negative symptoms (but not positive symptoms) and genotype (F1,85
between-subject = 4.69, p = 0.033)
Conclusions: To the best of our knowledge, this is the first imaginggenetics
study of NRXN1, and the first pharmacogenetic study of the
putative functional rs1045881 polymorphism. Our findings
demonstrate that the NRXN1 gene, a vulnerability gene for SCZ and
ASD from both candidate gene studies and genome-wide CNV scans,
influences brain structure and cognitive function. In conjunction with
our in silico results, our findings provide evidence for
neurobiological and cognitive susceptibility mechanisms by which
the NRXN1 gene confers risk factors potentially for schizophrenia.
Our pharmacogenetic findings suggest that the rs1045881 NRXN1
polymorphism may influence clozapine response. NMDA receptor
function may be a common factor for schizophrenia, and clozapine
response.
48
OPS3.4 NRGN GENE, A GENOME-WIDE SUPPORTED
SCHIZOPHRENIA RISK VARIANT, MODULATES
PREFRONTAL CORTICAL INFORMATION PROCESSING
DURING WORKING MEMORY
ECIP
A. Rauch*, R. Rasetti, J. Callicott, F. Zhang, B. Kolachana, Q. Chen,
J. Apud, V. Mattay, D. Weinberger
Genes, Cognition and Psychosis Program, Clinical Brain Disorders
Branch, National Institute of Mental Health, National Institutes of
Health
*rauchav@mail.nih.gov
Introduction: A single nucleotide polymorphism (SNP)-based GWA
study by Stefansson et al. (Nature, 2009) found a significant
association of schizophrenia with a SNP (rs12807809) located
upstream of the neurogranin gene (NRGN) on 11q24.2. The gene
product of NRGN is a postsynaptic protein kinase substrate that binds
calmodulin in the absence of calcium. NRGN may play a role as
CaM reservoir and it is important for calmodulin's activation of
CaMKinase II which is part of NMDA receptor signaling. Animal
studies showed that this gene product is involved in cognitive
functions including memory processing. To date there have been no
studies exploring the influence of the NRGN gene on memory related
cortical information processing in humans. In the current study, we
explored the effect of rs12807809 genotype on neural circuits
underlying working memory (WM).
Methodology: 219 healthy Caucasian subjects without any history of
psychiatric illness were studied with BOLD functional Magnetic
Resonance Imaging (fMRI) while they performed a 2-back WM task.
DNA isolation and analysiswere conducted on blood samples
obtained from all subjects whogave informed consent according to
NIMH Institutional ReviewBoard guidelines. Neuroimaging data
were acquired on a GE Signa 3-T scanner (GE Systems, Milwaukee,
Wisconsin) and were analyzed using SPM5. Given the low
frequency of homozygous C allele carriers (6 subjects), they were
combined with the heterozygotes (CT + CC, 70 subjects) and
compared with subjects homozygous for the high frequency riskassociated
T allele (TT, 149 subjects). Effect of NRGN genotype (TT
vs C carriers) on brain activity during WM was assessed using a twosample
t-test.
Results: Age, gender, education, handedness, IQ, and task-related
variables (2- Back accuracy and reaction time) were not significantly
different between TT homozygotes and C carriers. There was
significantly increased activation in the Dorsolateral Prefrontal
Cortex (DLPFC) (BA9, xyz = 57 18 33, Z = 4.22, p = 0.008 and xyz
= -48 3 36, Z = 4.03, p = 0.019, both FWE-corrected within DLPFC
Region of interest) of the risk allele T homozygotes during 2Back
WM in comparison to the non-risk allele C carriers (CT + CC).
Conclusions: The relatively increased DLPFC activation observed in
this study in the risk allele T homozygote healthy individuals
implicates a phenomenon characterized as inefficiency in cortical
information processing and shown to be a neuroimaging intermediate
phenotype for genetic studies of schizophrenia. Our results suggest
that NRGN, like a number of other genes implicated in
schizophrenia, may be associated with clinical risk because of
modulating the efficiency of cortical memory circuitry.

ORAL PRESENTATIONS SESSION 4:
PHARMACOGENOMICS
OPS4.1 PHARMACOGENETICS OF ANTIDEPRESSANT
TREATMENT OUTCOME IN DEPRESSION - ROLE OF HPA
AXIS AND ADVERSE LIFE EVENTS
M. Ising*, S. Lucae, E. Binder, F. Holsboer, B. Mueller-Myhsok
Max Planck Institute of Psychiatry
*ising@mpipsykl.mpg.de
Introduction: While candidate gene studies suggested a strong
genetic component of treatment outcome in major depression, recent
genome-wide association studies (GWA) failed to identify consistent
effects. It is likely that genetic variations contribute to treatment
outcome in a concerted mode, which explains the low effect size if
only a single variant at a time is considered. Furthermore, genetic
factors explain only parts of the phenotype suggesting a role of other
factors including biomarkers and environmental influences.
Methodology: We conducted a GWA in patients from the Munich-
Antidepressant-Response-Signature (MARS) project and in a German
replication sample. A set of 328 single nucleotide polymorphisms
(SNPs) related to outcome in both GWA was genotyped in the
Sequenced-Treatment-Alternatives-to-Relieve-Depression
(STAR*D) study. We generated a multi-locus genetic variable
describing the individual number of alleles of the selected SNPs
("response" alleles) to evaluate additive genetic effects on
antidepressant treatment outcome. Then, we further tested the
moderating effects of adverse life events and of HPA axis measures
as biomarkers for treatment outcome.
Results: The multi-locus analysis revealed a significant contribution
of a binary variable categorizing patients as carriers of a high vs. low
number of response alleles in predicting antidepressant treatment
outcome in MARS and STAR*D. In addition, we observed that the
degree of normalization of a disturbed HPA axis regulation and the
experienced adversity of past life events further contributes to
treatment outcome depending on the individual risk genotype.
Conclusions: Our results demonstrate the importance of multiple
genetic factors in combination with HPA axis regulation and
environmental exposure to predict antidepressant treatment outcome
underscoring the multifactorial nature of this trait.
49
OPS4.2 GENOMICS OF SSRI TREATMENT OUTCOMES
FOR MAJOR DEPRESSIVE DISORDER: GENOME-WIDE
ASSOCIATIONS AND FUNCTIONAL GENOMICS
ECIP
Y. Ji*(1), J. Biernacka(1), S. Hebbring(1), Y. Chai(1), G. Jenkins(1),
K. Snyder(1), M. Drews(1), Z. Desta(2), D. Flockhart(2), T.
Mushiroda(3), M. Kubo(3), Y. Nakamura(3), N. Kamatani(3), D.
Schaid(1), R. Weinshilboum(1), D. Mrazek(1)
1. Mayo Clinic 2. Indiana University 3. RIKEN Center for Genomic
Medicine
*ji.yuan@mayo.edu
Introduction: Functional genomics in pursuit of susceptibility loci
for psychiatric disorders and response to therapy represents a
complementary strategy to genetic association studies, which is
especially important when genomic replication studies are
challenging.
Methodology: We performed a genome-wide association study
(GWAS) for citalopram/escitalopram treatment outcomes (remission
and response) in major depressive disorder (MDD) using DNA from
529 patients recruited to an SSRI clinical trial. After GWA analyses
of primary treatment outcomes, we functionally characterized 14
SNPs selected from SNPs with the lowest p-values (1.04 × 10 -6 to
8.33 × 10 -5 ) that were also near or within a gene. Two different
experimental methods that assess the possible effect of a SNP on
transcription, electrophoretic mobility shift (EMS) and reporter gene
assays, were performed.
Results: Functional genomic experiments showed that rs11144870
(OR = 0.423, p = 1.04×10 -6 ) in intron 2 of the riboflavin (vitaminB2)
kinase (RFK) gene on chromosome 9 and rs915120 (OR = 0.497, p =
1.15×10 -5 ) in intron 7 of the G protein-coupled receptor kinase
(GRK5) gene on chromosome 10 appeared to be functionally
significant based both on their ability to drive transcription and bind
nuclear proteins. Increased transcription of RFK by the variant allele
of rs11144870 may lead to reduced level of circulating vitamin B2, a
phenomenon that has been previously linked to depressive symptoms
in adults. Other potential candidate loci included a series of intronic
SNPs in the glucosaminyl (N-acetyl) transferase 1(GCNT1) gene,
and intergenic region close to the D-amino acid oxidase activator
(DAOA) gene and the 5-hydroxytryptamine (serotonin) receptor 1B
(HTR1B) gene.
Conclusions: Our study represents an attempt to join functional
genomics with GWAS data for SSRI treatment outcomes in MDD, a
step that might help to provide biological plausibility for observed
associations and to gain novel insights into underlying mechanisms.

OPS4.3 HTR2A VARIATION PREDICTS TREATMENT
RESPONSE TO VENLAFAXINE XR IN GENERALIZED
ANXIETY DISORDER
F. Lohoff*, T. Richardson, S. Narasimhan, P. Multani, B. Etemad, K.
Rickels
UPenn
*lohoff@mail.med.upenn.edu
Introduction: Generalized Anxiety Disorder (GAD) is a chronic
psychiatric disorder with significant morbidity and mortality.
Antidepressants are the preferred choice for treatment; however,
treatment response is often variable. Several studies in major
depression have implicated a role of the serotonin receptor gene
(HTR2A) in treatment response to antidepressants. We tested the
hypothesis that the genetic polymorphism rs7997012 in the HTR2A
gene predicts treatment outcome in GAD patients treated with
venlafaxine XR.
Methodology: Treatment response was assessed in 156 patients that
participated in a 6-month open label clinical trial of venlafaxine XR
for GAD. Primary analysis included HAM-A reduction at 6 months.
Secondary outcome measure was the CGI-I score at 6 months.
Genotype and allele frequencies were compared between groups
using chi-square contingency analysis.
Results: The frequency of the G-allele differed significantly between
responders (70%) and non-responders (56%) at 6 months (p=0.05)
using the HAM-A scale as outcome measure. Similarly, using the
CGI-I as outcome, the G-allele was significantly associated with
improvement (p=0.01). Assuming a dominant effect of the G-allele,
improvement differed significantly between groups (p=0.001,
OR=4.72). Similar trends were observed for remission although not
statistically significant.
Conclusions: We show for the first time a pharmacogenetic effect of
the HTR2A rs7997012 variant in anxiety disorders, suggesting that
pharmacogenetic effects cross diagnostic categories. Our data
document that individuals with the HTR2Ars7997012 SNP G-allele
have better treatment outcome over time. Future studies with larger
sample sizes are necessary to further characterize this effect in
treatment response to antidepressants in GAD.
50
OPS4.4 A GENE EXPRESSION AND PROTEOMIC STUDY
PROVIDE FURTHER EVIDENCE FOR THE INVOLVEMENT
OF SPERMIDINE/SPERMINE N(1)-ACETYLTRANSFERASE
(SSAT1) IN SUICIDE AND SUGGESTS NEW BIOLOGICAL
DETERMINANTS OF SUICIDAL BEHAVIOUR IN BIPOLAR
DISORDER PATIENTS
ECIP
A. Squassina*(1), M. Manchia(1,2), D. Congiu(1), M. Costa(1), G.
Severino(1), C. Chillotti(3), R. Ardau(3), A. Soggiu(4), C. Piras(5),
P. Roncada(6), P. Keddy(7), G. Robertson(7), M. Alda(2), M. Del
Zompo(1,3)
1. Laboratory of Molecular Genetics, Section of Clinical
Pharmacology, Department of Neurosciences “B.B. Brodie”,
University of Cagliari 2. Department of Psychiatry, Dalhousie
University 3. Unit of Clinical Pharmacology of the University
Hospital of Cagliari 4. Section of Neurophysiology and
Neurochemistry, Department of Neurosciences “B.B. Brodie”,
University of Cagliari 5. Department of Zootechnical Science,
University of Sassari 6. Istituto Sperimentale L. Spallanzani 7.
Laboratory of Molecular Neurobiology, Department of
Pharmacology, Sir Charles Tupper Medical Building, Dalhousie
University
*squassina@unica.it
Introduction: Suicide is strongly associated with Major Affective
Disorders with a risk for completed suicide 6 to 15 times higher in
patients compared to the general population. Lithium is to date the
most effective treatment for bipolar disorder (BD) with a well
established protective effect against suicide. However, the
mechanisms responsible for these clinical effects remain unclear. So
far, several studies attempted to identify biological markers and genes
involved in suicide. A gene expression microarray study performed
using postmortem brain tissue by Sequeira et al. (2006) reported a
significant reduction in expression of the gene encoding the enzyme
spermidine/spermine N1-acetyltransferase 1 (SSAT1) in suicide
completers with and without depression compared to controls. This
result has been replicated by others.
Methodology: To confirm and extend these findings, we measured
SSAT1 gene expression levels in lymphoblastoid cell lines (LCLs)
from two populations (Sardinian, n = 41 and Canadian, n = 24) of BD
subjects characterized for suicidal behaviour and healthy controls. In
order to test the effect of lithium on SSAT1, each LCL was divided
into two lines cultured for 7 days in media with and without LiCl (1.0
mmol/l).
Results: SSAT1 expression was significantly increased by lithium in
LCLs from controls (p< 0.001) and in subjects with low (p < 0.001)
and high (p < 0.001) personal and genetic risk of suicide but not in
LCLs from suicide completers (p > 0.05). These findings were
replicated in the Canadian sample and the analysis on the pooled
dataset increased the power and the significance of our findings. In
contrast with the gene expression findings the protein study showed
that SSAT1 levels were significantly decreased when comparing each
of the 3 groups at different risk of suicide with controls. This could
suggest a compensatory effect in the pathway of polyamine system.
These differences were reduced or disappeared by lithium treatment
in vitro. On the other hand, no differences were shown when
comparing groups with different risk of suicide either with or without
lithium treatment in vitro. The proteome analysis also highlighted
several proteins differentially expressed in at least one of the
comparisons or according to lithium treatment. These proteins are
currently being identified and results will be presented at the
conference.
Conclusions: In conclusion, our findings suggest that suicide
completers might represent a distinct group of patients with an altered
SSAT1 function.

OPS4.5 BERBERINE AND EVODIAMINE INFLUENCE
SEROTONIN TRANSPORTER (5-HTT) EXPRESSION VIA
THE 5-HTT-LINKED POLYMORPHIC REGION
ECIP
Y. Hu*(1), E. Ehli(1,2), J. Hudziak(3), G. Davies(1,2)
1. Avera Institute for Human Behavioral Genetics, Avera Behavioral
Health Center 2. Department of Psychiatry, Sanford School of
Medicine, University of South Dakota, 3. Department of Psychiatry,
College of Medicine, University of Vermont
*yueshan.hu@avera.org
Introduction: The serotonin transporter (5-HTT) regulates the
serotonin transmission process via the modulation of extracellular
fluid serotonin concentrations, which in turn regulates mood,
emotion, and appetite. Studies including ours have demonstrated that
the natural compounds berberine and evodiamine reduce food intake.
Berberine also has antidepressant-like effects with the possible mode
of action attributed to the regulation of serotonergic
neurotransmission. Until recently the serotonin transporter genelinked
polymorphic region (5-HTTLPR) which controls the
transcriptional activity of 5-HTT, was reported to contain three
alleles (S, LG, LA) and had been demonstrated to be associated with
varying therapeutic responses to antidepressant treatment.
Interestingly, our group has recently discovered and functionally
characterized three novel 5-HTTLPR alleles: XS11, XL17, XL18.In this
present study, the effect of berberine and/or evodiamine on 5-HTT
expression and its promoter activity in a serotonergic neuronal cell
line RN46A was investigated. The aim of the study was not only to
elucidate the potential mode of action of berberine and evodiamine
on the serotonergic system but also provide an example of the role of
pharmacogenetics in herbal medicine.
Methodology: Real-time RT-PCR was used to measure the mRNA
expression of 5-HTT in RN46A neuronal cells. Protein expression of
5-HTT was determined by western blotting. Promoter activity of 5-
HTT was analyzed by dual-luciferase reporter (DLR) assay with
plasmid constructs containing the six 5-HTTLPR alleles (S, XS11, LG,
LA, XL17, and XL18 alleles).
Results: The results showed that 100 µM berberine increased 5-HTT
expression by 2.9 fold and treatment with 2 µM and 4 µM
evodiamine increased 5-HTT expression by 0.7 fold and 1.5 fold
respectively. Analysis of 5-HTT protein expression revealed that
treatment with either 100 µM berberine or 2 µM evodiamine, alone or
in combination increased 5-HTT protein expression by 0.6 fold, 0.9
fold and 1.2 fold respectively. The treatment of the individual alleles,
(S, XS11, LG, LA, XL17, and XL18 ), with 100 µM berberine increased
5-HTT promoter activity by 67%, 128.7%, 106.9%, 100.4%, 26.2%,
and 82%, and treatment with 2 µM evodiamine increased 5-HTT
promoter activity by 216.7%, 81.6%, 305.6%, 181.5%, 175.3%, and
102.2% respectively. Furthermore, treatment of S allele, with 100 µM
berberine combined with 2 µM evodiamine increased promoter
activity (315.3%) more than treatment of 100 µM berberine (62.8%),
or 2 µM evodiamine (250.5%) alone.
Conclusions: Both berberine and evodiamine alone and in
combination increased 5-HTT mRNA and protein expression
significantly. More interestingly, berberine and evodiamine increased
5-HTT promoter activity differently depending on the genetic
variation of the 5-HTTLPR polymorphism. This study has provided a
convincing example of how herbal compounds influence the
expression of one of the most intensively studied psychiatric
candidate genes, the serotonin transporter.
51
ORAL PRESENTATIONS SESSION 5: GWAS/CANDIDATE
GENES I
OPS5.1 A GWAS OF PSYCHOSIS - DATA FROM THE
PSYCHOSIS ENDOPHENOTYPES CONSORTIUM
E. Bramon*, K. Lin, C. Lewis, M. Arranz, R. Murray, J. Powell
Institute of Psychiatry - King's College London
*elvira.bramon-bosch@kcl.ac.uk
Introduction: Psychotic disorders including schizophrenia, bipolar
and schizo-affective disorders affect approximately 2% of the general
population. Epidemiological data show they are heritable and it is
believed thousands of genes of small effect interacting with
environmental risk factors are involved (McGuffin, 2007 Sullivan et
al., 2003 Purcell et al, 2009). Through genome-wide association
studies (GWAS) a number of promising loci are being identified for
schizophrenia and bipolar disorder and there is growing evidence for
a shared genetic architecture between diverse mental disorders
(Rujescu et al., 2009 Stefansson et al., 2008 Huang et al., 2010 Owen
et al., 2010 Owen et al., 2011 PGC, 2009 Sullivan et al., 2009
Williams et al., 2010).We set out to do a GWAS looking at a broad
phenotype of psychosis in a multi-centre sample from Europe and
Australia.
Methodology: All participants underwent a structured clinical
interview with either the SADS, SCID or SCAN to ascertain a DSM-
IV diagnosis of schizophrenia, schizo-affective disorder or bipolar
disorder with a history of psychotic symptoms. Controls underwent
the same assessments to rule out a personal or family history of the
listed disorders. Family history was explored in all participants using
the semi-structured FIGS interview. Participants were excluded if
they had a history of neurological disease or head injury resulting in
loss of consciousness. After quality control 4,661 participants (1,195
cases, 797 unaffected relatives and 2,669 controls), 721,331 SNPs
and 5 PCA covariate vectors were used for analysis. As part of the
Wellcome Trust Case Control Consortium, these samples were
genotyped using Affymetrix 6.0. A genome-wide association analysis
was conducted in the program UNPHASED (Dudbridge, 2008). This
package allows for the combined analysis of case-control and family
study data, thus maximizing the statistical power of this sample.
Results: We have identified several SNPs that cross genome-wide
significance levels for association with psychosis as a broad
phenotype. We found a promising SNP in the CUX2 gene reaching
genome wide significance (p=10 -8 ), with further significant
associations in multiple neighbouring proxy SNPs and with previous
independent evidence of association with bipolar disorder and autism
(Glaser et al, 2005 Kato 2007). As in previous research (Sullivan,
2010 Williams et al, 2011), we have identified loci in the HLA region
in chromosome 6 showing association with psychosis (p=10 -5 - 10 -7 ).
Our current findings are preliminary and await replication in an
independent sample.
Conclusions: These data contribute to the international effort to
produce a large enough sample to investigate psychosis. We intend to
study a selection of biological markers of brain function and structure
that are relevant in psychosis, which should increase the power to
detect associations.

OPS5.2 THE NEURONAL TRANSPORTER GENE SLC6A15
CONFERS RISK TO MAJOR DEPRESSION
S. Lucae*(1), M. Kohli(1), P. Saemann(1), M. Schmidt(1), M.
Alexander(2), S. Ripke(1), F. Holsboer(1), B. Müller-Myhsok(1), E.
Binder(1)
1. Max Planck Institute of Psychiatry 2. Institute of Human Genetics,
Department of Genomics, Life&Brain Center, University of Bonn
*lucae@mpipsykl.mpg.de
Introduction: Major depression (MD) is one of the most prevalent
psychiatric disorders and a leading cause of loss in work productivity.
A combination of genetic and environmental risk factors likely
contributes to MD. We present data from a genome-wide association
study revealing a neuron-specific neutral amino acid transporter
(SLC6A15) as a novel susceptibility gene for MD.
Methodology: We performed a genome-wide case-control study in a
stringently selected sample of MD inpatients of a tertiary clinic in
Munich, Germany, and matched controls devoid of any lifetime
psychiatric diagnoses. We performed replication of the results of the
GWAS in six additional independent samples of German, Dutch,
United Kingdom and African American origin. The herein reported
association results are based on an overall sample size of 15,089
unrelated individuals. To further characterize the functional relevance
of the identified locus, we analyzed genotypic influences of
associated SNPs on pre-mortem human hippocampus and
lymphoblastoid cell line expression profiles. We also employed in
vivo high resolution structural magnetic resonance imaging (MRI)
with a focus on the hippocampal formation.
Results: A meta-analysis conducted across all 7 samples resulted in a
genome-wide significant association with a p-value of 1.41e-09 for
the recessive model of rs1545843 and an estimate of an OR = 1.398
(95% CI 1.254-1.557). Homozygote carriers of the A-allele of this
SNP had a higher risk to suffer from depression and depressive
symptoms compared to carriers of the two other genotypes. Risk
allele carrier status in humans and chronic stress in mice were
associated with a downregulation of the expression of this gene in the
hippocampus, a brain region implicated in the pathophysiology of
MD. The same polymorphisms also showed associations with
alterations in hippocampal volume and neuronal integrity.
Conclusions: Decreased SLC6A15 expression, due to genetic or
environmental factors might alter neuronal circuits related to the
susceptibility for MD. Our convergent data from human genetics,
expression studies, brain imaging and animal models suggest a novel
pathophysiological mechanism for MD that may be accessible to
drug targeting.
52
OPS5.3 AKAPS INTEGRATE GENOME-WIDE
ASSOCIATION STUDY FINDINGS FOR AUTISM
SPECTRUM DISORDERS
ECIP
G. Poelmans*(1), B. Franke(2,3), J. Glennon(1), D. Pauls(4), J.
Buitelaar(1)
1. Department of Cognitive Neuroscience, Donders Institute for
Brain, Cognition and Behaviour, Radboud University Nijmegen
Medical Centre 2. Department of Human Genetics, Radboud
University Nijmegen Medical Centre 3. Department of Psychiatry,
Donders Institute for Brain, Cognition and Behaviour, Radboud
University Nijmegen Medical Centre 4. Psychiatric and
Neurodevelopmental Genetics Unit, Center for Human Genetic
Research, Massachusetts General Hospital, Harvard Medical School
*g.poelmans@psy.umcn.nl
Introduction: Autism spectrum disorders (ASDs) are highly
heritable. In recent years, six genome-wide association studies
(GWASs) of ASDs were published. Integration of the findings of
such studies can provide further insight into the genetic etiology of
ASDs.
Methodology: In order to identify genetic networks, bioinformatics
and systematic literature analyses were conducted for 200 genes from
five published GWASs that yielded association with ASDs through
single nucleotide polymorphisms (SNPs) at P < 0.0001. The sixth
published GWAS was used to validate the findings. We also searched
for overlap between the identified candidate genes and genes located
in copy number variations (CNVs) in people with ASDs and we
identified microRNAs that downregulate the expression of ASD
candidate genes and are dysregulated in ASDs.
Results: A total of 117 of the 200 ASD candidate genes encode
proteins fitting into three signalling networks regulating
steroidogenesis, neurite outgrowth and synaptic function, and we
were able to place 35 other ASD candidate genes - including strong
ASD candidates such as CNTNAP2, MET and NRXN1 - in the
identified networks. Importantly, the proteins encoded by 10 ASDlinked
AKAP (A-kinase anchor protein) genes functionally integrate
signalling cascades within and between these networks. Lastly, we
found that 79 of the 200 ASD candidate genes were found in CNVs
in people with ASDs and 100 genes were targets of ASD-implicated
microRNAs.
Conclusions: We have identified three signalling networks for ASDs
that provide an important contribution to our understanding of the
molecular basis of the disorder and that are functionally integrated by
AKAPs, ‘druggable' proteins that deserve further attention as possible
targets for psychopharmacological treatment of ASDs.

OPS5.4 GENOME-WIDE GENE EXPRESSION STUDY OF A
SCHIZOPHRENIA DATASET
A. Sanders*(1), H. Göring(2), E. Drigalenko(2), J. Shi(3), W.
Moy(1), J. Freda(1), J. Jacobi(1), D. He(1), M. Collaboration(4), J.
Duan(1), P. Gejman(1)
1. NorthShore University HealthSystem, and University of Chicago
2. Texas Biomedical Research Institute 3. National Cancer Institute 4.
Molecular Genetics of Schizophrenia (MGS) Collaboration
*alan.sanders.md@gmail.com
Introduction: Large schizophrenia case-control GWAS have found
common-variant low-effect loci with most signals being intergenic or
intronic, rare large-effect CNVs, and also evidence for polygenic
contributions to schizophrenia. Each type of variant may regulate
mRNA expression as their functional mechanism, but previous work
examining expression has been hampered by underpowered samples.
Methodology: We selected EBV-transformed LCLs derived from
968 European ancestry case samples and 968 screened controls with
pre-existing GWAS data from MGS. We grew the selected LCLs
with intermixed cases and controls, used standardized conditions, and
extracted total RNA. We have assayed mRNA from the first half of
the sample with Illumina HT-12v4 microarrays, and are now assaying
the remainder using RNAseq. We have studied and controlled for
known confounding effects (e.g., age, sex, ancestry, growth rate,
energy status, transformation site, viral load), as well as unknown
confounders with an expression principal components analysis (PCA)
approach. We used regression analysis to identify transcripts
differentially expressed by affection status and will be performing
eQTN analyses.
Results: We present here the results from our gene expression
experiment with 446 of 968 cases and 457 of 968 controls, i.e. the
portion of the sample studied with microarray. After stringent quality
control, we retained 27,118 transcripts and no sample was identified
as an outlier (all were retained). Examining carriers for
schizophrenia risk CNVs at the 1q21.1, 15q13.3, 16p11.2, and
22q11.21 loci showed the predicted copy number effects for welldetected
RefSeq genes: deletions showing lower expression than the
normal diploid copy number in 78% of the transcripts within the
CNV boundaries, and of duplications with higher expression 49% of
the time. After a genome-wide Bonferroni correction, we found 569
differentially expressed transcripts representing 509 genes,
distributed genome-wide, especially at the chromosome 6p histone
cluster located within the MHC region, where the cases showed
consistent histone downregulation. An alternative analytical strategy
incorporating only known confounders (i.e., not using the expression
PCA approach) resulted in fewer genome-wide significant findings,
but similarly converged on histones of the MHC region.
Conclusions: It is highly provocative that the most prominent
expression result here is also the most significant schizophrenia
GWAS locus (i.e., MHC), a result which strongly suggests that LCLs
are a useful cell model for studying expression in schizophrenia, and
suggest this may be the case for some other psychiatric
disorders. We will present interim analyses for the remaining half of
the sample (studied by RNAseq), including assessing inter-method
consistency and for artifacts of either method, both for overall results
and in ~50 samples assayed with both microarrays and RNAseq. We
will also present our eQTNs analyses, and discuss their relevance for
explaining genetic contributions to schizophrenia.
53
OPS5.5 A RIGOROUS FAMILY-BASED REPLICATION
STUDY OF SCHIZOPHRENIA GWAS FINDINGS
K. Åberg(1), Y. Liu(2), J. Bukszár(1), J. McClay JL(1), S.
consortium(1), P. Sullivan(2), E. van den Oord*(1)
1. VCU 2. UNC
*ejvandenoord@vcu.edu
Introduction: The aim of this study was to identify genetic variants
involved in Schizophrenia (SCZ).
Methodology: We first performed a meta-analysis of 18 SCZGWAS
(~22,000 subjects from European ancestry). Using a novel
statisticalframework we developed, we then identified six data bases
(a linkage meta-analysis, brain transcriptome meta-analysis,
schizophrenia candidate gene data base, OMIM, expression QTL
database) that appeared informative about SCZgenetics. These
informative data bases were integrated in the meta-analysis to
identify the most promising SCZcandidate SNPs and genes. Finally,
9,400 selected SNPs were genotyped in 6,300 independent samples
from 1,900 nuclear families. Prior to analyses, we subdivided
subjects into ancestralgroups based on IBS sharing between founders.
Family-based association tests were performed within each group and
a “meta-analysis” was performed by combining test statistics across
all groups.
Results: Results showed enrichment of small p-values in subjects
from European, Asian, and African ancestry (average fold increase of
medium p-value equaled 1.19, 1.12, and 1.07 respectively) as well as
the meta-analysis involving all three groups (fold increase medium pvalue
1.15). Even though some of the SNPs had p-values with ranks
up to 100,000 in the GWAS meta-analysis, SNPs selected after data
integration replicated equally well or even better compared to SNPs
with the smallest p-values but that were not implicated by multiple
data sources. The top SNPs from our replication study had p-values
in the 10 -4 -10 -6 range and included severalcoding region SNPs. We
were also able to replicate variants in TCF4 and NOTCH4 that have
previously been associated with SCZ. Forty-eight SNPs (3 times
more than expected) from the MHCregion had p-values < 0.01 in
patients from European ancestry but did not replicate in the other
ethnic groups. This pattern of replication can be explained by the fact
that our GWAS meta-analysis involved subjects from European
ancestry only and that LD structure and disease architecture is known
to be highly population specific for the MHCregion.
Conclusions: Our results supported a polygenic architecture for
SCZas multiple genes with small effects replicated.

ORAL PRESENTATIONS SESSION 6: NEXTGEN
SEQUENCING
OPS6.1 WHOLE-EXOME SEQUENCING OF FIVE
FAMILIES WITH BIPOLAR DISORDER
F. Goes*(1), M. Pirooznia(1), J. Parla(2), M. Kramer(2), E.
Elhaik(3), A. Chakravarti(3), R. Karchin(4), P. Zandi(5), W.
McCombie(2), J. Potash(1)
1. Johns Hopkins University School of Medicine, Dept. of Psychiatry
2. Cold Spring Harbor Laboratory 3. Johns Hopkins University
School of Medicine, Institute of Genetic Medicine 4. Johns Hopkins
University, Dept. of Biomedical Engineering 5. Johns Hopkins
Bloomberg School of Public Health, Department of Mental Health
*fgoes1@jhmi.edu
Introduction: Complex disorders such as bipolar disorder (BP) are
likely to harbor both common and rare susceptibility alleles. While
common variation has been widely studied in the last decade,
identification of rare variants has only recently become feasible with
second-generation sequencing. In this study, we employ wholeexome
sequencing to identify rare coding variants that segregate in
five families with BP.
Methodology: Exome sequencing was performed in 30 individuals
from five multiplex BP families using solution-based capture and
paired-end sequencing on the Illumina GA II. Alignment and variant
calling were performed with BWA, SAM tools and GATK. SNVs
were annotated with SeattleSeq and SWISS-PROT databases, and the
SCHISM (Supervised CHaracterization of Inherited SNPs and
Mutations) algorithm. Each family was analyzed individually by
selecting novel variants that were predicted to be damaging and
segregated with disease.
Results: Mean coverage for the targeted exome sequence was 97% at
1X coverage, 91% at 10X and 62% at 40X. A total of 41,154
variants were identified, including 3,340 novel variants. Of these, 52
were nonsense and 2,027 were missense variants, of which 504 were
predicted to be damaging to protein function. In the within-family
analysis, we found 16 novel damaging missense variants that
segregated with BP.
Conclusions: Our initial results show that a family-based analysis
with multiplex pedigrees can successfully winnow novel variants to a
relatively small number that segregate within families. These
preliminary analyses provide evidence for 16 novel variants that may
be associated with familial BP. These variants are currently being
genotyped in an additional 1000 BP cases and 1000 controls, and the
results will be presented at the WCPG.
54
OPS6.2 FAMILY-BASED EXOME SEQUENCING IN
FAMILIES MULTIPLY-AFFECTED FOR SCHIZOPHRENIA
J. Rosenfeld*(1,2), A. Malhotra(1,2), T. Lencz(1,2)
1. Zucker Hillside Hospital 2. Feinstein Institute for Medical
Research
*jrosenfeld@nshs.edu
Introduction: Schizophrenia is a highly heritable disease, yet recent
genome-wide association studies have demonstrated that common
polygenic alleles cannot fully account for the observed inheritance.
Recently, the exomes (the entire gene-coding region of the genome)
of individuals affected with a variety of Mendelian diseases have
been sequenced to identify rare, highly penetrant mutations
underlying the pathology of those particular cases. Since
schizophrenia (like other complex disorders) is likely to have a subset
of cases caused by rare protein-coding changes, exome sequencing
may be a useful approach, particularly in multiply-affected families
in which several individuals may share a single causative mutation.
Methodology: We have completely sequenced the exomes of two
families that are multiply affected with schizophrenia. Each family
consisted of two affected individuals and either two or four
unaffected first degree relatives. The exome of each individual was
captured using the Agilent SureSelect technique and then sequenced
on a single lane of the Illumina HiSeq sequencer with 100 bp pairedend
reads. The exomes were analyzed to determine many different
kinds of variations including SNPs, rearrangements and copy-number
variations (CNV). We utilized existing computational tools for the
SNP detection, while the rearrangement and CNV detection were
performed using our own newly created tools.
Results: High-quality, high-depth reads were obtained on 75% of the
exome, with a median of 80x depth. Initial analysis of the first family
indicates that there were an average of 20,000 SNPs per
individual. After filtering the variants, ~200 missense mutations and
3 nonsense mutations shared by cases and absent in unaffected family
members. Results from all 10 individuals will be presented at the
meeting.
Conclusions: We have utilized exome sequencing to identify
mutations underlying the schizophrenia in two families. The overall
genetic similarity of family members enhances the ability to pinpoint
the variations by eliminating family-specific mutations that are
irrelevant to disease status. Candidate mutations will then be tested in
a larger panel of cases and controls to eliminate false positives and
determine frequency and penetrance of potentially causative
mutations.

OPS6.3 BRAIN TRANSCRIPTOME ANALYSIS BY RNA-SEQ
REVEALS NOVEL DIFFERENTIALLY EXPRESSED GENES
IN BIPOLAR DISORDER
N. Akula*(1), J. Wendland(1), G. Laje(1), K. Choi(2), M.
Webster(3), H. Bravo(4), S. Detera-Wadleigh(1), F. McMahon(1)
1. Mood and Anxiety Disorders Section,Human Genetics Branch,
National Institute of Mental Health, National Institutes of Health 2.
Department of Psychiatry and Program in Neuroscience, Uniformed
Services University of the Health Sciences, Center for the Study of
Traumatic Stress 3. Stanley Lab of Brain Research 4. Center for
Bioinformatics and Computational Biology, University of Maryland
*akulan@mail.nih.gov
Introduction: RNA-seq is a relatively new technique that leverages
high-throughput sequencing technologies to provide estimates of
transcript abundance at a precision not previously realized in
hybridization-based microarray assays. RNA-seq also enables the
detection of novel, low abundance transcripts, allele-specific
expression, alternative splicing, and post-transcriptional
modifications, such as RNA editing. This technique thus provides a
fundamental context in which risk alleles can be evaluated for their
impact on gene expression and co-regulation. In a preliminary study,
we used RNA-seq to characterize the brain transcriptome in bipolar
disorder.
Methodology: We performed deep-sequencing (~130M paired-end
reads) of high quality total RNA (RNA-integrity number ≥ 7)
extracted from prefrontal cortex obtained post-mortem from 4 cases
diagnosed with bipolar I disorder and 5 age- and sex-matched,
psychiatrically-healthy controls, provided by the Stanley Medical
Institute. Library preparation, fragmentation and PCR enrichment of
the target RNA was followed by paired-end sequencing on the
Illumina GA-IIx system. The resulting reads were mapped and
aligned to the reference genome (hg18) using TopHat (Trapnell et al.
2009). Preliminary analysis of differential expression of known
(NCBI-RefSeq and Ensemble) and alternate transcripts was
performed using Cufflinks (Trapnell et al. 2010), in parallel with
analysis with HTSeq (http://wwwhuber.embl.de/users/anders/HTSeq/)
and DESeq (Anders and Huber
2010) analysis. Transcripts with raw counts ≤ 50 were excluded from
downstream analysis. Significant differentially expressed transcripts
were identified based on a p-value ≤ 0.05, adjusted for multiple
testing. These transcripts were further analyzed in DAVID (Dennis et
al. 2003; Huang da et al. 2009) in order to detect enriched functional
groups of genes.
Results: A total of 172 transcripts were differentially expressed by as
much as tenfold; of these 154 transcripts were down-regulated in
bipolar disorder. Differentially-expressed transcripts showed
significant enrichment of the Gene Ontology terms “neuronal
development,” “apoptosis,” “G-protein coupled receptors,” and
“calcium ion homeostasis.”
Conclusions: Further analyses to identify novel alternate transcripts
that are differentially expressed in bipolar disorder brain are
underway. These preliminary results demonstrate that RNA-seq may
reveal gene expression changes in biologically-relevant pathways that
were not detected consistently in previous microarray-based
expression profiling studies.
55
OPS6.4 ROBUST DISCOVERY OF COPY NUMBER
VARIATION IN MATCHED SWEDISH SCHIZOPHRENIA
CASE-CONTROL WHOLE-EXOME TARGETED
SEQUENCING
ECIP
M. Fromer*(1), J. Moran(1), K. Chambert(1), P. Sullivan(2), C.
Hultman(3), P. Sklar(1,4,5), S. Purcell(1,4)
1. Stanley Center for Psychiatric Research, Broad Institute of
Harvard and MIT 2. Departments of Genetics, Psychiatry, and
Epidemiology, University of North Carolina at Chapel Hill 3.
Department of Medical Epidemiology and Biostatistics, Karolinska
Institutet 4. Center for Human Genetic Research, Massachusetts
General Hospital 5. Division of Psychiatric Genomics, Mount Sinai
School of Medicine
*fromer@broadinstitute.org
Introduction: There has been much recent debate regarding the
genetic architecture underlying susceptibility to schizophrenia and
other neuropsychiatric diseases. Nonetheless, it is clear that rare
copy number variations (CNV) play a role in the pathology of
schizophrenia. Most work on this topic has been done using predefined
single-nucleotide polymorphism (SNP) arrays. In order to
more fully elucidate this phenomenon at higher genomic resolution
and identify rare CNV (both deletions and duplications), we have
undertaken high-coverage whole-exome targeted resequencing of 550
matched Swedish schizophrenia cases and controls. Specifically, we
use the high-coverage sequencing read depth as a proxy for copy
number, so that we would like to identify regions where a particular
sample has significant depletion or enrichment in sequenced reads
and infer a deletion or duplication CNV, respectively.
However, this effort is confounded by multiple known factors,
including GC content of the targeted exome intervals, the size and
sequence complexity of these intervals, sequencing batch, proximity
to segmental duplications, and nucleotide-level population variation,
all of which may lead to differential capture of exomic sequence or
sequencing efficiency. Moreover, there are presumably multiple
unknown factors and interactions between all such factors that lead to
sample-specific variability in read depth that does not directly result
from genomic copy number variation.
Methodology: In order to overcome these issues, we have performed
rigorous statistical, data-driven normalization using a principal
component analysis (PCA) approach. We detected and removed read
depth variation driven by these factors, resulting in a de-noised data
set with which we then proceeded to make CNV calls using a hidden
Markov model (HMM) algorithm for segmentation of the exome into
diploid, deletion, and duplication regions for each sample.
Results: Overall, we achieved high sensitivity in recovering CNV
calls based on Affymetrix 6.0 SNP array data for these same
samples. Moreover, we were able to detect a large number of
previously unknown rare CNVs with nominally significant
association with susceptibility to schizophrenia, where a number of
these CNV were in brain-expressed genes.
Conclusions: We conclude that high-coverage exome sequencing
and careful analysis of sequencing depth can provide valuable
insights into the location and character of rare CNV conferring risk
for schizophrenia, and, more generally, provides a broadly applicable
tool for both sensitive and specific CNV discovery.

OPS6.5 IDENTIFICATION AND ANALYSIS OF RARE
VARIATION IN 503 PUTATIVE SCHIZOPHRENIA RISK
LOCI IN 1876 SAMPLES BY TARGETED RESEQUENCING
C. O'Dushlaine(1,2), J. Moran(2), D. Ruderfer(1,2), K. Chambert(2),
P. Lichtenstein(3), C. Hultman(3), P. Sullivan(4), S. Purcell(1,2),
P. Sklar(1,2,5)
1. Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts
General Hospital 2. Stanley Center for Psychiatric Research, Broad
Institute of Harvard and MIT 3. Department of Medical
Epidemiology, Karolinska Institutet 4. Departments of Genetics,
Psychiatry, and Epidemiology, University of North Carolina at
Chapel Hill 5. Division of Psychiatric Genomics, Department of
Psychiatry, Mount Sinai School of Medicine
Introduction: We performed array-based sequence capture followed
by next generation sequencing to analyze 503 genes identified via
genomic studies. These genes were chosen from regions that contain
highly penetrant copy number variants in autism, schizophrenia, and
bipolar disorder (1q21.1, 15q11.2, 15q13-13.3, 16p11.2, 16p12.1,
17p12 and 22q11.21; n=197 genes). Genes were also selected for the
following reasons: within CNVs identified as highly connected
through GRAIL analysis (n=32), presence in a gene locus strongly
associated with schizophrenia (n=17), and bipolar disorder (n=6),
identified as potentially enriched in rare variants through exome
sequencing (n=117), identified as enriched in pathway analyses of
GWAS data (n=20), or found in a region of excess runs of
homozygosity (n=11).
Methodology: Case and control DNA pools were carefully
constructed from a Swedish schizophrenia sample collection to
decrease the likelihood of population stratification. Pools contained
only a single sex to allow for sequencing of X-chromosome genes.
Blood-derived DNAs were normalized and pooled with 20 DNA
samples per pool. An Agilent SureSelect custom-designed
oligonucleotide array was synthesized and used for solution-based
hybrid selection on each pool. Captured products were then
sequenced by Illumina GA using 76 bp paired-end reads. The hybrid
selection array design included exons as well as microRNAs within
CNV regions or in genes. In total 1.56Mb, encompassing 7095 exons
from 503 RefSeq genes (including 12 microRNAs and 18 miR137regulated
genes) were sequenced in 1876 samples (938 cases, 938
controls).
Results: We present findings from this study for single variant and
gene-based (variable threshold) association tests. In particular, we
find evidence for association for the calcium channel genes
CACNA1H, CACNA1S and for the 3p21 genes ITIH3 and NEK4. We
address analytic challenges inherent in the analysis of rare variants.
Conclusions: *The authors acknowledge the support of an
Anonymous Foundation, the Stanley Medical Research Institute and
the National Institutes of Mental Health.
56
ORAL PRESENTATIONS SESSION 7: STATISTICAL
GENETICS, GENETIC EPIDEMIOLOGY
OPS7.1 CNR1 GENOTYPE MODERATES THE EFFECTS OF
CHILDHOOD ABUSE ON ANHEDONIA
A. Agrawal*(1), E. Nelson(1), A. Littlefield(2), K. Bucholz(1), L.
Degenhardt(3), A. Henders(4), P. Madden(1), N. Martin(4), G.
Montgomery(4), M. Pergadia(1), K. Sher(2), A. Heath(1), M.
Lynskey(1)
1. Washington University School of Medicine, Psychiatry 2.
University of Missouri in Columbia 3. Burnet Institute 4. Queensland
Institute for Medical Research
*arpana@wustl.edu
Introduction: Endocannabinoids, primarily, Narachidonoylethanolamine
(anadamide) and 2-arachidonoylglycerol
(2-AG) are naturally occurring molecules that have putative
anxiolytic, analagesic and anti-depressant effects. Their influence is
partly mediated by the CB1 receptors to which they bind. Recent
studies have found that rodents with deficiencies in CB1 receptor
activity (due to targeted knock-out or antagonist action) show
anhedonia and depressed mood. In addition, there is accumulating
evidence that persistent stress directly contributes to differential
fluctuations in anadamide and 2-AG. In rodents experiencing
repeated stress exposure, decline in anadamide can modify
corticosteroid levels, indicating the endocannabinoid signaling may
be critical in adaptation to stress. While the theories linking
endocannabinoids to stress adaptation and mood have been validated
in rodent models, there are no human studies that clearly demonstrate
the nature of this relationship. We hypothesized that a variant in the
gene encoding the human endocannabinoid receptor (CNR1) -
rs1049353 - interacts with childhood exposure to serious physical
abuse to produce anhedonia.
Methodology: Logistic regression was used to examine the
association between anhedonia and the main effects of and
interaction between rs1049353 and childhood physical abuse in four
independent samples. Sample A consisted of 1140 female twins from
Missouri, Sample B consisted of 1934 heroin dependent cases and
controls from Australia, Sample C consisted of 203 Missouri college
aged students with and without a family history of alcoholism and
Sample D consisted of 1740 Australian general population twins. All
subjects were of European-American descent. Anhedonia was
defined as self-reported loss of interest in activities considered
enjoyable and childhood physical abuse was also defined using a
variety of self-report items.
Results: In Sample A, there was a strong main effect of childhood
physical abuse on anhedonia but not main effect of genotype.
However, the interaction was significant (P=0.03). While 22% of the
full sample reported anhedonia, 58% of individuals who were
homozygous for the major allele (GG) and experienced abuse
reported anhedonia compared with 28% of carriers of the minor allele
(AA/AG) experiencing abuse with no differences between AA and
AG individuals. When stratified by genotype, there was no main
effect of abuse on anhedonia in AA/AG individuals indicating that
rs1049353 buffers the potent impact of childhood physical abuse on
anhedonia. This interaction was systematically replicated in Samples
B, C and D.
Conclusions: This is one of few replicated examples of genotype x
environment interaction that further underscores the role of the
endogenous cannabinoid system in buffering the pathogenic effects
of childhood abuse on mental health. Consistent with the preclinical
literature, our association directly replicated evidence from rodent
models and validates the important role of cannabinoid receptors in
modulation of mood.

OPS7.2 ASSESSING THE CONTRIBUTION FAMILY DATA
CAN MAKE TO CASE-CONTROL STUDIES OF RARE
VARIANTS
D. Curtis*
Barts and the London School of Medicine and Dentistry
*david.curtis@qmul.ac.uk
Introduction: When pathogenic variants are rare then even among
cases the proportion of subjects possessing a variant might be low,
meaning that very large samples might be required to conclusively
demonstrate evidence of an effect.Relatives of subjects within a casecontrol
sample might provide useful additional information.
Methodology: The method of model-free linkage analysis
implemented in MFLINK was adapted to incorporate linkage
disequilibrium (LD) parameters in order to model a putative
pathogenic variant in complete LD with a disease locus. The
performance of the method was tested against other methods applied
to case-control samples. The effect of adding in to the analysis
relatives of cases and controls found to carry the variant was
investigated.
Results: The method produced similar results to other methods when
applied to case-control samples. When affected siblings or cousins of
cases possessing the variant were incorporated they had a large effect
on the results obtained. The evidence for involvement increased or
reduced as expected, depending on whether or not the relatives
themselves were found to possess the variant. The size of the effect
was large relative to that expected from just increasing the size of a
standard case-control sample.
Conclusions: Affected relatives offer a valuable resource to assist the
interpretation of case-control studies of rare variants. The method is
capable of including other relative types and can deal with complex
pedigrees.
57
OPS7.3 A POISSON REGRESSION APPROACH FOR
ASSOCIATION MAPPING OF COUNT PHENOTYPES
S. Ghosh*, A. Chakrabortty
Indian Statistical Institute
*saurabh@isical.ac.in
Introduction: Clinical end-point traits are often characterized in
terms of quantitative endophenotypes. Since these phenotypes carry
more information on within-genotype variability, it has been argued
that analyzing quantitative precursors may be a more powerful
strategy to identify novel genetic factors underlying a complex
disorder. The statistical methods of choice for association mapping of
quantitative phenotypes based on population-level data have been
Analysis of Variance (ANOVA) or the Kruskal Wallis test. However,
both these methods are strictly suited to analyze continuous traits. For
psychiatric disorders, traits such as symptom counts often serve as
endophenotypes of interest for understanding the genetic basis of the
clinical end-point trait. Since such traits are discrete in nature, it may
not be optimal to use ANOVA or the Kruskal Wallis test to detect
association.
Methodology: For population level data, we propose a Poisson
regression approach that computes the likelihood of the count
phenotype conditional on an additive allele count at a SNP. The test
statistic is asymptotically distributed as chi-squares with one degree
of freedom under no association between the SNP and the
phenotype. For family-based data involving trios with at least one
heterozygous parent at a SNP, we use a similar Poisson regression
model conditional on two indicator variables: the marker allele
transmitted by the heterozygous parent and the marker allele
transmitted by the other parent. A one degree of freedom test based
only on the coefficient of the first indicator is protected against
population stratification as it tests for association in the presence of
linkage. A two degrees of freedom test based on both the indicators is
also a valid test for association, but is susceptible to population
stratification.
Results: We have performed extensive simulations under different
genetic models to compare the relative performance of the proposed
Poisson regression with ANOVA and the Kruskal Wallis test for
population level data. We find that while the asymptotic tests for
ANOVA and Kruskal Wallis yield an inflated rate of false positives,
especially when there is heteroskedasticity in the distribution of the
trait across the QTL genotypes, our proposed method maintains the
correct size. Moreover, our method yields uniformly more power (for
equivalent empirical levels) compared to the other methods for the
different genetic parameters considered in our simulations. For a trio
design, we find that the powers are lower than a population-level
design where the number of sampled trios is equal to the number of
random individuals sampled. We applied our method to analyze an
endophenotype defined as the number of externalizing symptoms
associated with alcoholism using data generated in the Collaborative
Study On the Genetics of Alcoholism (COGA) project. We found
significant evidence of association in the class 1 alcohol
dehydrogenase subunit ADH1C in the 4q22.3 region.
Conclusions: The proposed Poisson regression model is ideally
suited for association analyses of count phenotypes and is more
powerful compared to existing approaches such as ANOVA or the
Kruskal Wallis test.

OPS7.4 EVALUATION OF PERMUTATION-BASED
APPROACHES FOR MULTI-MARKER ASSOCIATION
V. Moskvina*(1), K. Schmidt(2), A. Vedernikov(1), M. Owen(1), N.
Craddock(1), P. Holmans(1), M. O'Donovan(1)
1. School of Medicine, Cardiff University 2. School of Mathematics,
Cardiff University
*moskvinav1@cf.ac.uk
Introduction: Genome-wide association studies have revealed a
small number of genome-wide significant associations for psychiatric
disorders. Since there is clear evidence for a substantial contribution
to risk from variants that are tagged by GWAS arrays (ISC, 2009),
the most likely explanation for this is limited power of the studies to
date. Until larger studies are conducted, one possible approach to
increasing power is to conduct set-based analyses to test the
collective effect of larger groups of SNPs, for example a set of
markers within a single gene (Moskvina et al, 2009), the hypothesis
being that under a polygenic model, there may be multiple
independent signals within a single gene. Several set-based methods
have been proposed, among which the most widely used are the
product of all p-values (ProdP) and the average of the chi-square
statistics (as in PLINK, Purcell et al, 2007), but the most powerful
method has yet to be determined. The major challenge for set based
analyses is to allow for marker-marker correlations (LD) and
therefore typically, the significance of set-based analyses is assessed
by permutations to adjust for this.
Methodology: To compare the performance of the permutation based
ProdP test (which gives similar results to the average chi-square) with
those of the Hotelling's T 2 test (HT 2 ) proposed by Chapman &
Whittaker (2008) and logistic regression analysis, neither of which
require permutations, in simulated and real data. We also investigated
the effects of LD on the results obtained, as an appropriate method
would give identical results when additional markers in perfect LD
are included to those obtained when such markers are excluded.We
compared ProdP and HT 2 tests for simulated and real data. The HT 2
test is practically identical to logistic regression analysis without
covariates with all the markers included in the model. We therefore
focused on the HT 2 test for comparison with the ProdP method. We
applied both methods to simulated data with varying numbers of
SNPs in tight LD, and also to real GWAS data comprising 11791
genes with two or more SNPs (the WTCCC bipolar dataset). We
tested the effect of pruning SNPs by LD i.e. selecting markers at
random and removing those which are in LD with the selected ones
above a certain threshold value of r 2 .
Results: In the presence of even modestly correlated markers, the
HT 2 and ProdP tests are broadly correlated but give very different
individual gene-wide p-values. As markers become less dependent
(i.e. more aggressive LD pruning), the results of the two tests
converge, but this occurs at quite a low r 2 threshold for pruning
(r 2 =0.05). We also show that in a real dataset, when markers are LD
pruned at this threshold, there is considerable loss in power, as would
be expected if there are multiple signals within gene sets arising from
SNPs that are partially correlated, or single true signals that are
partially tagged by multiple SNPs, each conferring additional
partially independent information.
Conclusions: We show that in the presence of marker-marker LD at
a level typical in GWAS datasets, gene-wide tests statistics derived
from the HT 2 approach are more valid and more powerful than those
derived from permutations. Unless markers are aggressively LD
pruned, which risks loss of power, the HT 2 (and regression based
approaches) are recommended over the customary approaches that
rely on permutations.
58
OPS7.5 UNDERESTIMATED EFFECT SIZES IN GWAS:
FUNDAMENTAL LIMITATIONS OF SINGLE SNP
ANALYSIS FOR DISEASE STATUS
ECIP
S. Stringer*(1), N. Wray(2), R. Kahn(1), E. Derks(1)
1. Rudolf Magnus Institute of Neuroscience 2. Queensland Institute
of Medical Research
*s.stringer@umcutrecht.nl
Introduction: Psychiatric traits are often highly heritable. Only a
small proportion of the heritability can be explained by observed
genetic variants in traditional genome-wide association (GWA)
studies. We propose an additional explanation for the missing
heritability in disease status by showing that effect sizes can be
severely underestimated with single SNP analysis.
Methodology: We defined a model of complex disease based on the
multi-locus odds model with four model parameters: prevalence,
effect size, risk allele frequency, and number of effect SNPs. We
used this model to simulate the odds ratios that would be obtained
with single SNP analysis and studied the relationship between true
effect size and estimated effect size. We derived the same
relationship for a model of continuous disease trait based on a multilocus
linear model. Finally, we derived the relationship between
biased effect size estimates and missing heritability.
Results: Moderate to large effect sizes of causal variants may be
estimated as relatively small effect sizes in single SNP association
testing. This underestimation effect is most severe for diseases
influenced by multiple risk variants and results in an increased
missing heritability. Continuous disease traits generated with linear
genetic models are not affected by the underestimation effect.
Conclusions: Single SNP association methods test for association at
a single SNP at a time, and thus test across an averaged genetic
background. The non-linearity of the relationship between genetic
risk and disease risk results in biased estimates of effect size. As
many GWA studies of psychiatric traits apply single SNP analysis to
disease status, their results could underestimate true effect sizes and
reduce the explained variance. Therefore, when a multi-locus model
of disease risk is assumed, single SNP analysis is ill-suited for
identifying large effect sizes. Instead, we recommend analyzing all
SNPs simultaneously.

ORAL PRESENTATIONS SESSION 8: GWAS/CANDIDATE
GENES II
OPS8.1 META-ANALYSIS OF EUROPEAN AND ASIAN-
ANCESTRY SAMPLES IDENTIFIES 3 NOVEL LOCI
ASSOCIATED WITH BIPOLAR DISORDER
ECIP
D. Chen*(1), X. Jiang(1), N. Akula(1), J. Wendland(1), C. Steele(1),
L. Kassem(1), J. Park(2), N. Chatterjee(2), S. Jamain(3), A.
Cheng(4), M. Leboyer(3), P. Muglia(5), T. Schulze(1,6), S.
Cichon(7), M. Rietschel(8), F. McMahon(1)
1. Human Genetics Branch, National Institute of Mental Health
Intramural Research Program, National Institutes of Health, U.S.
Dept of Health and Human Services 2. Division of Cancer
Epidemiology and Genetics, National Cancer Institute, National
Institutes of Health, US Department of Health and Human Services 3.
Inserm U955, Department of Psychiatry, Groupe Hospitalier Henri
Mondor-Albert Chenevier, AP-HP, Université Paris Est, Fondation
FondaMental 4. Institute of Biomedical Sciences, Academia Sinica 5.
Department of Psychiatry, University of Toronto & NeuroSearch 6.
Section on Psychiatric Genetics, Department of Psychiatry and
Psychotherapy, University Medical Center, Georg-August-
Universität 7. Institute of Neuroscience and Medicine (INM-1),
Structural and Functional Organization of the Brain, Genomic
Imaging, Research Center Juelich, D-52425 Juelich, Germany
Department of Genomics, Life & Brain Center, University of Bonn,
D-53127 Bonn, Germany 8. Department of Genetic Epidemiology in
Psychiatry, Central Institute of Mental Health, University of
Mannheim, D-68159
*chend4@mail.nih.gov
Introduction: Meta-analyses of bipolar disorder (BD) genome-wide
association studies (GWAS) have identified several genome-wide
significant signals in European-ancestry samples, but so far these
seem to account for little of the inherited disease risk.
Methodology: We performed a meta-analysis of over 750,000 highquality
genetic markers on a discovery sample of about 15,000
subjects of European and Asian ancestry. The most significant
findings were further tested in a replication sample of 3,800 cases and
controls. We then assessed the expression of associated gene(s) after
exposing cells in culture to pharmacological treatments for
BD. Based on these results and other established risk loci, we
estimated the number of susceptibility loci and effect size distribution
in BD, according to the method described by Park and colleagues
(2010).
Results: The results suggest novel association findings near the
genes TRANK1 (LBA1), LMAN2L, and PTGFR. The most significant
SNP, rs9834970 near TRANK1, was significant at the p=2.4 x 10 -11
level under a fixed-effects model. Supportive evidence for prior
association findings near ANK3 and a locus on chromosome 3p21
was also observed. After addition of the replication samples to the
meta-analysis, the overall picture was similar, although the
heterogeneity test became significant for several SNPs. In cultured
cells, valproate markedly increased TRANK1 expression in a dose-
and time-dependent manner.
Conclusions: These results support previous GWAS findings and
add new candidate genes to a growing list of bipolar disorder risk
loci, confirming the critical importance of sample size in GWAS
methods.
59
OPS8.2 ASSOCIATION WITH SYNE1 VARIANT IN BOTH
BIPOLAR DISORDER AND RECURRENT MAJOR
DEPRESSION
E. Green*(1), D. Grozeva(1), I. Jones(1), L. Jones(2), L. Forty(1), K.
Gordon-Smith(1,2), A. Farmer(3), P. McGuffin(3), J. Moran(4), J.
Kranz(4), S. Purcell(4), P. Sklar(4), M. Owen(1), M. O'Donovan(1),
N. Craddock(1)
1. MRC Centre for Neuropsychiatric Genetics and Genomics, Dept.
of Psychological Medicine, Cardiff University 2. Dept. of Psychiatry,
University of Birmingham 3. MRC SGDP Centre, Institute of
Psychiatry, King's College London 4. Stanley Centre for Psychiatric
Research, Broad Institute
*greenek@cf.ac.uk
Introduction: The bipolar disorder psychiatric GWAS consortium
reported last year a combined analysis of 16,737 individuals
including 7,481 individuals affected with bipolar disorder (BD) and
9,250 control individuals. In addition to confirming the association of
SNPs (single nucleotide polymorphisms) in ankyrin 3 (ANK3), a
genome-wide significant association was found in the region of
SYNE1 and its brain-expressed splice variant CPG2 (Pgc = 4.3 x 10 -8
OR = 1.15)
Methodology: We have genotyped a total of 2592 control individuals
(1579 independent of the WTCCC (Wellcome trust case control
consortium) BD GWAS), 1542 Independent BD cases and 1194
unipolar recurrent major depression cases (UP) in the SNP rs9371601
using the Sequenom iPLEX Gold technology.
Results: An association was seen with rs9371601 in SYNE1 with the
same risk in both the independent BD case control sample (1542 BD
and 1579 controls) with a Trend P value of 0.008, OR = 1.15, and
the UP samples (1194 UP and all controls 2592) Trend P value =
0.02, OR = 1.11.
Conclusions: Our study supports the association of SYNE1 in an
independent BD sample. We also found that the risk allele conferred
increased risk for recurrent major depression with similar effect size
to bipolar disorder.

OPS8.3 GWAS ANALYSIS ACROSS FIVE PSYCHIATRIC
ILLNESSES: RESULTS OF A COMBINED DATASET
POWER OF 56,867 INDIVIDUALS
S. Ripke*(1,2,3), B. Neale(1,2,3)
1. MGH 2. Broadinstitute 3. PGC - CrossDisorderGroup
*ripke@atgu.mgh.harvard.edu
Introduction: One of the primary goals of the Psychiatric GWAS
Consortium (PGC) was to explore the genetic overlap across
psychiatric phenotypes. Specifically, we began with 5 core
psychiatric illnesses: autism (AUT), attention deficit/hyperactivity
disorder (ADHD), bipolar disorder (BPD), major depression disorder
(MDD), and schizophrenia (SCZ). We amassed an unprecedented
sample size with power equivalent to 56,867 independent individuals
of European ancestry (N = 31,035 cases / 25,832 controls), derived
from five distinct diseases: MDD (9,229 / 7,347), BIP (6,988 /
4,859), SCZ (9,372 / 7,815), AUT (3,499 / 3,864), ADD (1,947 /
1,947). For AUT and ADHD, the majority of samples are familybased,
but we have represented the effective case-control sample size.
Methodology: After technical and genetic quality control and
successive imputation using Hapmap - Phase 3 as reference a
common dataset of 56,867 individuls with dosages on 1.3 million
SNPs was obtained. We conducted two primary analyses to assess
genetic overlap across diseases. To identify sharing at a composite
level, we applied polygene-analysis as described by the ISC 1 . After
demonstrating significant sharing across these phenotypes, we then
proceeded to conduct the primary single locus meta-analysis using a
SE-weighted approach combining evidence from each of the distinct
diseases. Beyond these two primary analyses, we conducted a range
of post hoc tests to dissect the top signals and understand the
structure of the risk for each of the individual diseases. We have also
endeavored to identify a replication set, even though identifying such
a cohort that reflects the construction of our initial set is challenging.
1 International Schizophrenia Consortium: Common polygenic
variation contributes to risk of schizophrenia and bipolar
disorder.Nature. 2009 Aug 6460(7256):748-52.
Results: Here we confirmed multiple previously described genes
from either single-disease studies or previously performed crossdisorder
studies. Specifically, we identify genome-wide significant pvalues
within ITIH3/4 (3p21), MIR-137 (1p21), MHC
(6p21), CACNA1C (12p13), CACNB2 (10p12), CNNM2 (10p24)
and TCF4 (18q21). Many genes within regions of suggestive pvalues
are under further investigation. Some results of the mentioned
secondary analyses will also be presented here.
Conclusions: Cross-disorder analyses are providing promising
results for the understanding of psychiatric illness. Such work,
however, is only successful in the face of careful combination of
datasets. To achieve this the Cross-Disorder-Subgroup of the PGC
has identified and solved many of these issues.
60
OPS8.4 FIVE NOVEL SUSCEPTIBILITY GENES
IDENTIFIED FOR ALZHEIMER'S DISEASE
D. Harold*, P. Hollingworth, R. Sims, A. Gerrish, J. Chapman, M.
Owen, J. Williams, G. Consortia
Cardiff University
*harolddh@cardiff.ac.uk
Introduction: In 2009 we published a genome-wide association
study (GWAS) of Alzheimer's disease (AD) in which we identified
two new genome-wide significant susceptibility loci: CLU and
PICALM. However we also observed more variants with P< 1×10 -5
than expected by chance. These included SNPs at CR1 and BIN1, loci
which have subsequently shown genome-wide significant association
with AD. In an attempt to identify new common susceptibility
variants for AD we have undertaken a three-stage association study
comprising 19,870 cases and 39,846 controls. We also genotyped
these samples at loci showing suggestive evidence for association in
the American Alzheimer's Disease Genetic Consortium (ADGC)
GWAS.
Methodology: In Stage 1, we performed a meta-analysis of four AD
GWAS datasets (6,688 cases and 13,685 controls). SNPs showing
association at P

OPS8.5 IDENTIFICATION OF COMMON VARIANTS
INFLUENCING PROTEIN ABUNDANCE LEVELS IN
ALZHEIMER’S DISEASE
A. Lourdusamy*(1), K. Lunnon(1), P. Proitsi(2), J. Powell(2), A.
Stewart(3), S. Williams(3), S. Lovestone(1,2), R. Dobson(1)
1. NIHR Biomedical Research Centre for Mental Health, South
London and Maudsley NHS Foundation Trust & Institute of
Psychiatry, Kings College London 2. MRC Centre for
Neurodegeneration, King's College London, De Crespigny Park 3.
SomaLogic, Inc. 2945 Wilderness Place, 80301
*anbarasu.lourdusamy@kcl.ac.uk
Introduction: Alzheimer’s disease (AD) is a common
neurogenerative disorder with a substantial genetic component.
Recent genome-wide association studies (GWAS) have identified
many gene variants that alter the risk of AD but the effects of these
variants are likely to be small 1,2,3 . Plasma protein abundance levels in
AD may be biologically relevant endophenotypes and the analysis of
genetic variants that influence protein levels may provide a
complimentary approach to GWAS leading to a greater
understanding of disease mechanisms.
Methodology: We measured protein abundance levels of 822
proteins in the plasma of 303 subjects from AddNeuroMed study
comprising cases, normal elderly controls and well as those suffering
mild cognitive impairment (MCI) approximately half of which
convert to AD within 2 years. Using the genotypes from these
subjects, we tested both the main SNP effects (genetic) and
diagnosis-SNP interaction (diagnostic) effects on the association of
486,402 SNPs with protein abundance levels as quantitative traits.
Results: We identified many local (cis) genetic effects including
SNPs in or near the SIGLEC9 (p = 7.23 x 10 -93) , FCGR2A (p = 1.50
x 10 -88 ), PDGFRB (p = 8.99 x 10 -79 ), IL6R (p = 2.62 x 10 -48 ), and
TNC (p = 4.23 x 10 -40 ) genes. Interestingly, we identified several
distant (trans) genetic effects of the NPS gene, 9 SNPs in or near
NPS are associated with different proteins, the most significant
association is with PSMA1 (p = 1.69 x 10 -13 ), and two SNPs of ABO
gene associated with the protein levels of SELE (p = 3.07 x 10 -18)
and CD209 (p = 8.21 x 10 -17 ). Many SNP – protein associations
were identified for the AD diagnostic effects including a SNP from
TIMP3 associated with EPHA5 protein levels (rs137484, p = 9.58 x
10 -18 ), SNP from FTO associated with DMP1 (p = 1.20 x 10 -16 ), and
a SNP in APBB2 associated with MMP10 (rs10003861, p = 2.62 x
10 -12 ).
Conclusions: These results suggest that the use of protein abundance
levels as intermediate quantitative traits in GWAS may provide
powerful approach for the identification of AD disease loci.
61
ORAL PRESENTATIONS SESSION 9: MIXED TOPICS
OPS9.1 GENES TO BIOLOGY…AND BACK TO
BEHAVIOR: UNDERSTANDING TRAJECTORIES OF RISK
FOR ALCOHOL DEPENDENCE
D. Dick*
Virginia Commonwealth University
*ddick@vcu.edu
Introduction: As the field makes progress in identifying genes
involved in complex psychiatric and substance use outcomes, the
next challenge is to better understand how identified genes contribute
to the manifestation of complex clinical disorders. This talk will
present an overview of the integration of gene identification efforts
with twin studies and longitudinal community-based projects in order
to understand and map the complex pathways from gene to clinical
disorder, with focus on the development of alcohol-related problems.
Methodology: Data from the Finnish twin studies, which are
population-based epidemiological samples with assessments
spanning ages 12 to 26, demonstrate the changing influence of
genetic effects on alcohol use and related phenotypes across
adolescence into young adulthood, and as a function of the
environment. We use this information to test hypotheses about the
risk associated with specific, identified genes (emerging from the
Collaborative Study of the Genetics of Alcoholism COGA) using
community-based samples of individuals studied longitudinally. To
this end, data will be presented from the Child Development Project,
a community-based study of ~500 children followed annually from
age 5-25 the Mobile Youth Study, an on-going community-based
sample of children ages 10-18 from high-risk, impoverished
neighborhoods in Mobile, Alabama and the Avon Longitudinal Study
of Parents and Children, an epidemiological cohort of ~10,000
children enrolled when their mothers were pregnant and assessed
yearly -- prenatally through young adulthood.
Results: We find that genes associated with adult alcohol
dependence in COGA (GABRA2, CHRM2) are associated with
behavior problems earlier in development, and that these associations
are moderated by environmental characteristics. Predisposing genes
show a stronger association with problematic outcomes under
conditions of poor parental monitoring and higher peer
deviance. Further, there appear to be different pathways to risk for
alcohol dependence, through a variety of impulsive and externalizing
characteristics.
Conclusions: Characterizing the risk associated with identified genes
in population and community-based samples will be necessary in
order to understand how genetic influences result in the eventual
alteration of risk for psychiatric and substance use outcomes. This
talk will demonstrate how, through interdisciplinary research, we are
gaining a greater understanding of how genetic and environmental
influences contribute to the risk for alcohol related problems, and
how that risk manifests across development.

OPS9.2 EXAMINING THE ASSOCIATION BETWEEN
GPSM1 AND HUMAN ALCOHOL DEPENDENCE USING
ASSOCIATION, BIOINFORMATICS, AND EXPRESSION
STUDIES
A. Adkins*(1,2,4), F. Aliev(1,3,4), O. McMichael(1,4), D.
Thiselton(1,3,4), C. Prescott(5), D. Dick(1,3,4), V.
Vladimirov(1,3,4), J. Bettinger(4,6), S. Bowers(1,3,4), K.
Kendler(1,3,4), B. Riley(1,3,4)
1. Virginia Institute for Psychiatric and Behavioral Genetics 2. Dept
of Human and Molecular Genetics 3. Dept of Psychiatry 4. Virginia
Commonwealth University 5. Dept of Psychology, University of
Southern California 6. Dept of Pharmacology and Toxicology
*adkinsae@vcu.edu
Introduction: Relapse, a hallmark of addiction, may result from
neuroadaptations in the brain during chronic drug use resulting in the
brain’s inability to function normally during periods of withdrawal.
Identifying genes within these pathways, and the biological basis of
their action, is of critical therapeutic interest. Model organism
studies can manipulate experimental conditions to mimic certain
aspects of the process of human withdrawal, craving and relapse. Gprotein
signaling modulator 1 (GPSM1) expression in rat nucleus
accumbens (NAc) increases following withdrawal from chronic
ethanol exposure and results in an increased, compulsive motivation
to seek ethanol (Bowers et al., 2008). The carefully constructed
experimental paradigm used in the study suggests results can be
compared to similar human phenotypes of craving and motivation to
drink alcohol. We investigated the role of GPSM1 in human Alcohol
Dependence (AD) and alcohol-related phenotypes using association
data and expression studies.
Methodology: Tag SNPs for the LD block surrounding GPSM1
(chr9: 138261561-138455700) were selected using HAPMAP and
Haploview. The Irish Affected Sib Pair Study of Alcohol
Dependence (IASPSAD) case-control sample (N=562 cases, N=569
controls) was genotyped and association analyses performed using
Haploview and Plink. Data for N=776 AD cases and affected siblings
from the IASPSAD and N=2000 Irish controls will be available
shortly. Standard primers were designed to uniquely amplify all 4
Refseq GPSM1 transcripts and real-time PCR run to assess RNA
levels in commercial RNA tissues (N=26). Human alcoholic (N=41)
and control (N=41) brain samples from the TRC in Sydney, Australia
will be examined for RNA expression of the 4 transcripts in the NAc
and 5 other brain regions.
Results: 2 of the 6 tag SNPs (rs10781510, rs3124994) were
significantly associated with AD (P=0.01, P=0.003) and DSM-IV AD
symptom 3 (P=0.009, P=0.004). Symptom 3 gauges if the subject
has ever had a drink when they promised they wouldn’t or have drank
more than intended. This phenotype suggests an increased or
uncontrollable motivation to drink (or craving) for alcohol that may
relate to the observed phenotype in rats. To further understand the
mechanism of action of GPSM1, expression levels of RNA were
assessed in multiple tissues. RNA levels of 4 different GPSM1
transcripts were measured in a commercial tissue panel. Work
measuring RNA levels of the transcripts in the TRC brain samples is
ongoing. C. elegans orthologs of GPSM1 will be knocked down and
mutants assessed for alcohol-related phenotypes.
Conclusions: Initial findings show an association between SNPs 5’
to GPSM1 and AD as well as a craving-like phenotype. This supports
studies in rats and suggests a role for GPSM1 in the neuroadaptations
contributing to relapse. Completion of RNA expression studies and
work in C. elegans will lead to a better understanding of the biology
of the system in which GPSM1 operates.
62
OPS9.3 COPY NUMBER VARIATION IN SCHIZOPHRENIA
AND BIPOLAR DISORDER IN A SWEDISH POPULATION
ECIP
S. Bergen*(1,3), C. O'Dushlaine(1,2,3), D. Ruderfer(1,2,3), S.
Akterin(4), J. Moran(3), K. Chambert(3), M. Schalling(5), U.
Ösby(5), M. Landen(4), E. Scolnick(3), P. Lichtenstein(4), C.
Hultman(4), P. Sullivan(6), P. Sklar(1,3,7), S. Purcell(1.2.3)
1. Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts
General Hospital 2. Analytic and Translational Genetics Unit,
Massachusetts General Hospital 3. Stanley Center for Psychiatric
Research, Broad Institute of Harvard and MIT 4. Department of
Medical Epidemiology and Biostatistics, Karolinska Institutet 5.
Department of Molecular Medicine and Surgery, Karolinska Institutet
6. Departments of Genetics, Psychiatry, and Epidemiology,
University of North Carolina at Chapel Hill 7. Division of Psychiatric
Genomics, Department of Psychiatry, Mount Sinai School of
Medicine
*sbergen@broadinstitute.org
Introduction: Several large, rare copy number variations (CNVs)
have now been associated with schizophrenia, but a clear picture has
yet to emerge for CNV involvement in bipolar disorder.
Methodology: We investigated CNVs in these disorders in a new
Swedish sample consisting of 1,506 individuals with schizophrenia
(SCZ), 834 with bipolar disorder (BD), and 2,089 controls. All
subjects were genotyped using the Affymetrix 6.0 array, and CNVs
were called using Birdsuite.
Results: In keeping with prior reports, deletions were enriched to a
greater extent in the SCZ sample. Deletions observed only once and
those of intermediate size, 200-500kb, were more frequent in both
case groups compared to controls (SCZ: p=.013, p=.019; BD: p=.017,
p=.046), while the largest CNVs, >500kb, were significantly enriched
only in the SCZ subjects (p=.0018). Duplications did not show
significant overrepresentation for either case group for any size or
frequency examined. Generally, more CNVs intersected genes in
SCZ than in controls, but this observation had less statistical support
in BD. Many large CNVs previously associated with SCZ and other
psychiatric and neurological conditions were observed in this sample
and, for these regions, duplications were observed more often than
deletions (N=88 vs. 47). SCZ subjects possessed significantly more
duplications at the 16p11.2 locus (p=.0012), and the 9q12-13 locus
showed similar CNV enrichment in SCZ (p=.0027). Other nominally
significant (p

OPS9.4 INVESTIGATING THE GENETIC BASIS OF
TOURETTE SYNDROME IN EUROPEAN POPULATIONS: A
MULTINATIONAL INITIATIVE
P. Paschou*, J. Karagiannidis, P. Aslanidou, E. Grigoriou, S.
Papasotiriou, V. Stathias,. The TSGeneSEE Initia
Dept. of Molecular Biology and Genetics, Democritus University of
Thrace
*ppaschou@mbg.duth.gr
Introduction: Tourette Syndrome (TS) is a neuropsychiatric disorder
of childhood onset, that is marked by multiple motor and vocal tics
and high comorbidity rates with obsessive compulsive disorder and
attention deficit and hyperactivity disorder. Although it was once
considered rare, a prevalence of 0.4-1% is currently reported. The
pathophysiological pathways leading to the onset of symptoms
remain poorly understood. However, it is thought that a complex
genetic background is involved, with multiple genes interacting with
environmental factors in order to lead to the onset of symptoms.
Multiple chromosomal loci have so far been implicated in the
etiology of the disorder. However, studies have been marked by the
difficulty to consistently replicate original positive findings.
Methodology: Undertaking a multinational effort, we have collected
one of the largest samples for the study of TS genetics that is
available to date. A total of 250 trios (one child affected with TS and
their parents) of Greek, Albanian, Italian, Polish, Hungarian, and
German origin were analyzed in order to attempt to replicate the
genetic association with regions that have been previously implicated
in TS etiology. Variation across SLITRK1, DAT1, MAOA, TPH2,
and the 17q25 region was investigated for association with the TS
phenotype. Furthermore, two novel candidates for TS susceptibility,
were also tested in our sample. The transmission test for linkage
disequilibrium was used in order to test for over- or undertransmission
of studied alleles to affected individuals. Both single
markers and haplotypic tests were performed.
Results: Our results reveal multiple positive signals of genetic
association. Over the past few years, association of TS etiology with
the SLITRK1 gene has become a subject of intense debate, with
many replication studies being unable to support original positive
findings of association with particular variants. Studying variation
across the gene, we show that the SLITRK1 gene may indeed be
involved in TS etiology in European populations, and even at a level
that was previously unappreciated. Meta-analysis of our results with
existing datasets, provides strong support for this hypothesis. On the
other hand, genes in the dopaminergic and serotonergic pathways, are
not significantly associated with the disorder in our sample.
Conclusions: Our results provide novel insights into the pathogenesis
of TS and support the hypothesis that different genetic factors may be
implicated in TS susceptibility across different populations, even
within Europe.
63
OPS9.5 POTENTIAL BENEFITS, RISKS, AND ETHICAL
APPLICATIONS OF PSYCHIATRIC GENETIC TESTING: A
PSYCHIATRIC GENETIC RESEARCHERS PERSPECTIVE
ECIP
J. Erickson*, M. Cho
Stanford University
*jessdae8@stanford.edu
Introduction: As genetic research rapidly advances, promising to
transform health care services, it is crucial to address the potential
social and ethical implications of this innovation. Mental health is
one of the fields that will be affected by these advancing
technologies. Although studies have explored potential benefits, risks
and ethical concerns regarding psychiatric genetic testing among
mental health professionals and potential users, there has been limited
focus on perspectives on these matters among the group who is
actively generating this knowledge, the psychiatric genetic
researchers. This work presents the results of an exploratory study
interviewing world-leading experts in psychiatric genetics research
who are conducting studies in depression, schizophrenia, and bipolar
disorder. Their input provides a needed addition to the ongoing
debate on how to incorporate psychiatric genetics research into
evolving health care settings in a realistic, safe, and ethical manner.
Methodology: Top experts in the field of genetics research for
bipolar disorder, major depression and/or schizophrenia were
contacted for a one-hour, audio-recorded interview. Twenty-five
psychiatric genetic researchers from 5 countries were interviewed
using a semi-structured interview guide focusing on participants’
beliefs about benefits, harms and ethical concerns that could result
from their work, and on suggested strategies for the ethical
implementation of their research into clinical practice. Interview
transcripts were imported into NVivo 9, and 3 trained researchers
coded the transcripts to assure a high coefficient of rater reliability
(Scott’s Pi > .90).
Results: The majority of respondents believed that the current state
of genetic research for BPD, schizophrenia, or depression is far away
from clinical utility. Three main barriers to the progression of this
research were identified as: lack of funding, the complexity of each
disorder, and the difficulty of following psychiatric patients. Subjects
classified the top 3 anticipated benefits from their research as: more
individualized medicine, earlier diagnosis, and de-stigmatization of
mental illness. Primary concerns voiced by interviewees about ethical
issues that could result from advancements in their research were the
premature commercialization of study results, a revival of eugenics,
and an increasing demand for prenatal psychiatric genetic testing.
Most interviewees opposed direct-to-consumer genetic testing for
psychiatric disorders and believed that psychiatrists should provide
patients with results. However, all participants agreed that physicians
are currently unprepared to interpret genetic results and suggested
strategies to prepare psychiatrists to use genetics research in a clinical
practice.
Conclusions: This preliminary analysis of psychiatric genetic
researchers’ views contributes a unique perspective to the growing
literature of stakeholder views on psychiatric genetic testing. Overall,
researchers expressed frustration with the progress of psychiatric
genetics research. They identified barriers to the progress of their
research and risks and ethical concerns resulting from this type of
work. However, they emphasized the need to continue with this line
of research due to the significant benefits genetics information will
provide. Interviewees also provided insights on the type of training
necessary to interpret tests. Being at the forefront of psychiatric
genetics research, these experts provided a well-informed and
realistic perspective regarding genetic testing for mental illness.

ORAL PRESENTATIONS SESSION 10: FUNCTIONAL
GENOMICS & MODEL ORGANISMS II
OPS10.1 HUMAN INDUCED PLURIPOTENT STEM CELL-
TECHNOLOGY TO STUDY NEURAL DIFFERENTIATION
ECIP
L. D'Aiuto*(1), A. Watson(1), M. Bamne(1), B. Heath(2), R. Di
Maio(3), G. Raimondi(4), V. Nimgaonkar(1)
1. Department of Psychiatry, University of Pittsburgh 2. Department
of Human Genetics, University of Pittsburgh 3. Department of
Neurology, University of Pittsburgh 4. Department of Immunology,
University of Pittsburgh
*daiutol@upmc.edu
Introduction: Neuronal Stem/Progenitor (NS/P) cells derived from
human induced pluripotent stem cells (iPSC) provide an
unprecedented opportunity to study human brain development and
model neurodegenerative and neurodevelopmental diseases. We have
initiated neurodevelopmental studies using human cytomegalovirus
(HCMV) as a tool to perturb normal neural differentiation. HCMV
infects neural stem cells and neuroprogenitor cells localized the in
ventricular and subventricular zones. It is a major cause of prenatal
encephalitis and mental retardation. HCMV has been investigated
using neurospheres prepared using forebrain tissues from fetal
abortuses. These models provide important information, but have
obvious limitations. Hence we have investigated CMV effects on
human iPSC-derived NS/P cells
Methodology: We generated iPSCs from adult human fibroblasts
obtained through adult skin biopsies. iPSCs were differentiated into
neurospheres that were expanded as monolayer cultures of NS/Ps.
The neurospheres were further differentiated into neurons stainable
with Tuj1, tyrosine hydroxylase, and NR4A2. Functional competency
was confirmed by live imaging of intracellular calcium influx. NS/P
cells and neurons were infected with human cytomegalovirus
(HCMV) at multiplicity of infection (MOI=3). Cell viability was
assessed by FACS analysis.
Results: Cytopathic effects of HCMV were observed on the 10th day
post infection in neuroprogenitor cells. Earlier, the adherence of these
cells to the underlying matrix was reduced. Neurons were much more
refractory to infection. Reduced cell density and shortening of
neuritic processes was only observed at day 15 post-infection. We are
now examining intracellular gene expression.
Conclusions: Human iPS cells can efficiently generate neurospheres,
which can be expanded as monolayer cultures of NS/P cells or
differentiated into neurons. iPSC-derived NS/P cells and neurons
offer powerful cellular models to investigate the effects of
neurotropic viral agents on human neurodevelopment.
64
OPS10.2 SYSTEMS GENETICS IN MOOD DISORDERS:
INTEGRATION OF GENOME-WIDE ASSOCIATION
RESULTS WITH HUMAN BRAIN EXPRESSION DATA
S. Detera-Wadleigh*, N. Akula, F. McMahon
National Institutes of Health
*deteras@mail.nih.gov
Introduction: Meta-analytic studies of genome-wide association
study (GWAS) data have shown significant association between
major mood disorders and genetic variants in the ANK3, CACNA1C
and PBRM1 gene regions (Ferreira et al. 2008 McMahon et al 2010
Liu et al. 2011). Modest statistical support for association has been
reported also for several genes in a meta-analysis of major depression
GWA data (Wray et al. 2010). In addition, a meta-analysis of 183
smaller studies that focused on 20 SNPs in 18 candidate genes
supported association in 6 genes. Differential gene expression in
brains from patients would provide an important functional correlate
to these findings. Since genes or their gene products act as
components of biological pathways, defects in these molecules would
cause cumulative and extensive system-wide perturbations that
impact on networks of interacting pathways, leading to pathology.
Methodology: We assembled a list of associated genes ranked by
level of support in GWAS and identified those that displayed
differential expression in postmortem brain obtained from cases with
a major mood disorder. We used several microarray-based
transcriptome datasets representing various brain regions from
patients with bipolar disorder or major depression as well as
psychiatrically-healthy controls (The Stanley Neuropathology
Consortium Integrative Database, http://sncid.stanleyresearch.org/).
To capture a glimpse of the pathways involved we used genes that
passed the association-expression integration analysis as seed for
network analysis. Networks were generated using the Michigan
Molecular Interaction (MiMI) plugin tool (Gao et al. 2009 Tarcea et
al. 2009) in Cytoscape (http://www.cytoscape.org/).
Results: The most stringent group, including ANK3, CACNA1C,
and PBRM1, formed two small networks. ANK3 and CACNA1C
node clusters were linked through 6 different nodes. (A node refers to
a protein or a gene in a network). PBRM1 formed a separate node
cluster. Functional annotation in DAVID Bioinformatics Resource
(http://david.abcc.ncifcrf.gov/home.jsp, NIAID/NIH) (Denis et al.
2003 Huang et al. 2009) revealed that ANK3 and CACNA1C nodes
were enriched for MAPK and beta adrenergic receptor pathways,
while the PBRM1 cluster was enriched for chromatin remodeling and
transcriptional regulation, consistent with its known function.
Lowering the stringency to include other genes led to the recruitment
of signaling pathways for neurotransmitter and hormone receptors,
neurotrophin, ErbB and the cell cycle.
Conclusions: Network analysis of genes that are implicated by both
GWAS and differential brain expression is a promising strategy for
identifying functional gene clusters and biological pathways involved
in the genetic risk for mood disorders.

OPS10.3 RNA-SEQ ANALYSIS OF DIFFERENTIATING
HUMAN NEURONS DERIVED FROM INDUCED
PLURIPOTENT STEM CELLS (IPSCS)
M. Lin(1), E. Pedrosa(2), A. Shah(2), D. Zheng(1,3,4),
H. Lachman*(2,5)
1. Department of Genetics Albert Einstein College of Medicine 2.
Department of Psychiatry Albert Einstein College of Medicine 3.
Department of Neurology Albert Einstein College of Medicine 4.
Department of Neuroscience Albert Einstein College of Medicine 5.
Department of Medicine Albert Einstein College of Medicine
*herb.lachman@einstein.yu.edu
Introduction: The development of patient-specific iPSCs for in vitro
disease modeling is a promising approach for studying the molecular
basis of SZ and other neuropsychiatric disorders. An especially useful
application of this technology is gene expression profiling using
patient-specific differentiating neurons. In the past, this analysis was
carried out on autopsy samples using microarrays. Live,
differentiating, patient-specific neurons has many advantages over
autopsy specimens and deep sequencing (RNA-Seq) is becoming the
method of choice for expression profiling over microarrays.
Methodology: iPSCs are being developed from controls and patients
with SZ with and without 22q11.2 deletions using standard protocols.
Neuronal differentiation was carried out using a protocol that
primarily yields glutamatergic neurons. RNA was extracted from
iPSCs and a small cluster of neurons. cDNA was synthesized and
amplified, and the samples were subjected to paired-end deep
sequencing using an Illumina GA2 next generation sequencing
platform.
Results: Our findings show that early differentiating neurons
undergo an extraordinary series of changes in gene expression and in
the generation of splicing isoforms. More than 2x10 8 reads were
obtained for both iPSCs and day 10 neurons. The expression of 9733
genes was significantly altered as the iPSCs differentiated into
neurons (p

OPS10.5 CONVERGENT FUNCTIONAL GENOMICS OF
ANXIETY DISORDERS: TRANSLATIONAL
IDENTIFICATION OF GENES, BIOMARKERS, PATHWAYS
AND MECHANISMS
A. Niculescu*(1), H. Le-Niculescu(1), Y. Balaraman(1), S. Patel(1),
M. Ayalew(1), J. Gupta(1), R. Kuczenski(2), A. Shekhar(1), M.
Geyer(2), N. Schork(3)
1. Indiana University School of Medicine 2. UC San Diego 3. Scripps
Research Institute
*anicules@iupui.edu
Introduction: Anxiety disorders are prevalent and disabling yet
understudied from a genetic standpoint, compared to other major
psychiatric disorders such as bipolar disorder and schizophrenia. The
fact that they are more common, diverse, and perceived as embedded
in normal life may explain this relative oversight. In addition, as for
other psychiatric disorders, there are technical challenges related to
the identification and validation of candidate genes and peripheral
biomarkers. Human studies, particularly genetic ones, are susceptible
to the issue of being underpowered, due to genetic heterogeneity, the
effect of variable environmental exposure on gene expression, and
difficulty of accrual of large well phenotyped samples. Animal model
gene expression studies, in a genetically homogeneous and
experimentally tractable setting, can avoid artifacts and provide
sensitivity of detection. Subsequent translational integration of the
animal model datasets with human genetic and gene expression
datasets can ensure cross-validatory power and specificity for illness.
Methodology: We have used a pharmacogenomic mouse model
(involving treatments with an anxiogenic drug- yohimbine, and an
anti-anxiety drug—diazepam) as a discovery engine for identification
of anxiety candidate genes as well as potential blood
biomarkers. Gene expression changes in key brain regions for
anxiety (prefrontal cortex, amygdala, hippocampus) and blood were
analyzed using a Convergent Functional Genomics (CFG) approach,
which translationally integrates our new data with published human
and animal model data, as a translational strategy of cross-matching
and prioritizing findings.
Results: Our work identifies top candidate genes(such as FOS,
GABBR1, NR4A2, DRD1, ADORA2A, QKI, RGS2, PTGDS,
HSPA1B, DYNLL2, CCKBR and DBP), brain-blood biomarkers
(such as FOS, QKI and HSPA1B), pathways (such as cAMP
signaling) and mechanisms for anxiety disorders -notably signal
transduction and reactivity to environment.
Conclusions: Overall, this work complements our previous similar
work (on bipolar mood disorders and schizophrenia) conducted over
the last decade. It concludes our programmatic first pass mapping of
the genomic landscape of the triad of major psychiatric disorders
using CFG, and permitted us to uncover the significant genetic
overlap between anxiety and these other major psychiatric disorders,
notably the under-appreciated overlap with schizophrenia. PDE10A,
TAC1 and other genes uncovered by our work provide a molecular
basis for the frequently observed clinical co-morbidity and
interdependence between anxiety and other major psychiatric
disorders, and suggest schizo-anxiety as a possible new nosological
entity.
66

POSTER SESSION I
ABSTRACTS
67

GENOMICS (GWAS, SEQUENCING)
PP1 THE PI3K-AKT-GSK3 SIGNALING PATHWAY AND
OVERLAPS BETWEEN SCHIZOPHRENIA AND BIPOLAR
DISORDER
F. Karege(1), A. Meary(2), N. Perroud(1), A. Carrard(1), F.
Schuroff(2), A. Malafosse*(1)
1. Geneva University Hospitals 2. Hopital Chenevrier-Mondor
*alain.malafosse@hcuge.ch
Introduction: Schizophrenia (SCZ) and Bipolar disorder (BPD) are
considered as different diseases in the diagnostic manuals. Genetic
studies suggest however, an overlap of these disorders. The PI3K-
Akt-GSK3ß signaling pathway is involved in cellular process such as
neurodevelopment. Its dysfunction could impact SCZ and BPD. We
aimed to investigate the PI3KC, PKB/AKT and GSK3 gene variants
and protein levels both in SCZ and BPD.
Methodology: This case-control study included 830 subjects of
European ancestry: 400 unrelated SCZ 230 unrelated BPD, and 200
unrelated healthy controls. Molecular genotyping of the following
genes was performed: Akt1, PI3KC3 and GSK3. SNPs and other
genetic variants were assessed. Additionally, postmortem brain
protein levels were assayed in deceased SCZ, BPD and matchedcontrols.
Lastly, an epigenetic study of DNA methylation on CpG
islands was assessed in Akt1 and GSK3 genes.
Results: For the Akt1 gene, the analysis identified a significant
global distortion in SCZ (P=0.0026) and in BPD (p=0.046). A
sliding window procedure showed a 5-SNP haplotype (TCGAG) to
be associated with SCZ (p=0.0001) and BPD (p=0.0041). Other
multi-SNP haplotypes also showed significant association with both
diseases. When SCZ and BPD were combined, the global p-value
improved (p=0.00001). For the GSK3ß gene, one SNP (rs6438552)
was found associated with the risk of SCZ (p=0.0008) and weakly
with BPD (p=0.06). With respect to controls, the PI3KC3 gene also
showed an association with one SNP (p=0.01) in SCZ and with a 2variants
(p=0.004) and a 3-variants (p=0.001) haplotype in both
disorders combined. In the epigenetic study, differential methylation
was found in CpG islands of GSK3ß genes from SCZ. On the basis of
selected Akt1 genotype, significant difference in protein expression
emerged between risk allele carriers and non carriers subjects
(p=0.02).
Conclusions: A number of genetic variants was found in both SCZ
and BPD. Furthermore, AKT and PI3KC protein levels were
decreased in brain (PFC) of SCZ and BPD. Preliminary data also
indicated a different GSK3ß gene methylation status in SCZ patients
compared to control subjects. This convergent evidence suggest an
alteration in the PI3K-AKT-GSK3 signaling pathway in both SCZ
and BPD. These findings support the role of this pathway in the
etiology of SCZ and BPD. The study is consistent with the overlap
model of these diseases.
68
PP2 A GENETIC ASSOCIATION STUDY AND COGNITIVE
FUNCTION ANALYSIS OF THE NEUROPILIN AND
TOLLOID-LIKE 1 GENE AND SCHIZOPHRENIA IN
JAPANESE POPULATION
M. Banno*(1), B. Aleksic(1,2), T. Koide(1), T. Kikuchi(1,3), K.
Kohmura(1), Y. Adachi(1), M. Ikeda(2), T. Inada(4), T. Iidaka(1), N.
Iwata(2), N. Ozaki(1)
1. Department of Psychiatry, Nagoya University Graduate School of
Medicine 2. Department of Psychiatry, Fujita Health University
School of Medicine 3. Matsuzaki Hospital 4. Department of
Psychiatry, Seiwa Hospital, Institute of Neuropsychiatry
*solvency@med.nagoya-u.ac.jp
Introduction: One of the major hypotheses for the pathophysiology
of schizophrenia is that numerous risk factors converge on the
hypofunction of the neurotransmitter glutamate resulting from the
antagonism of the N-methyl-D-aspartate (NMDA) receptor. This
hypothesis arises from observations that the NMDA receptor
antagonist phencyclidine can produce a psychotic condition similar to
the positive, negative, and cognitive symptoms of schizophrenia.
Methodology: We examined the association between schizophrenia
and neuropilin and tolloid-like 1 gene (NETO1), a postsynaptic
protein associated with the NMDAR complex. We selected 7 single
nucleotide polymorphisms (SNPs) in NETO1 region, which showed
nominal evidence for statistical significance based on the first GWAS
of schizophrenia conducted in Japanese population (JGWAS)
(case560, control548). Additionally, we included a SNP that was
shown to be associated with schizophrenia in the previous study (Shi,
J et al, Nature, 2009). We genotyped the 8 SNPs in the independent
replication sample comprised of 963 patients and 919 controls.To
complement genetic association findings we evaluated the effect of 8
SNPs on the cognitive performance measured by Continuous
Performance Test (CPT) and Wisconsin Card Sorting Test (WCST)
(case118, control104).
Results: There was no genetic association signal detected in the
independent replication sample after Bonferroni correction was
applied (lowest P=0.26). Furthermore, we did not detect any of the
common SNPs selected for our association study could affect scores
in CPT or WCST.
Conclusions: We conclude that common SNPs within NETO1 may
not increase the risk for schizophrenia in the Japanese subjects.
However, we cannot exclude the possibility that common SNPs of
smaller effect size or rare variants in NETO1 may increase the
susceptibility to schizophrenia.

PP3 AN ASSOCIATION STUDY OF TCF4
POLYMORPHISMS WITH SCHIZOPHRENIA IN JAPANESE
POPULATION
T. Kaneko*(1), T. Kanazawa(1), S. Kawashige(2), A. Tsutsumi(1),
J. Koh(1), H. Yoneda(1)
1. Osaka Medical College 2. Ozone Hospital
*psy078@poh.osaka-med.ac.jp
Introduction: TCF4 gene (transcription factor 4, on 18q21.2) is a
member of the basic helix-loop-helix (bHLH) transcription factor
family. TCF4 regulates gene expression by hetero-dimerization with
other transcription factors in the brain during development, while it
regulates the development of lymphoid progenitors to the B- and Tcell
lineages and plasmacytoid dendritic cell (PDC) differentiation.
Mutation inTCF4 cause an autosomal-dominant neurodevelopmental
disorder, Pitt-Hopkins Syndrome. Recently, meta-analysis
of GWAS reported rs9960767 on intron 4 of TCF4 was associated
with schizophrenia in Caucasians (p=4.1×10 -9 , Stefansson et
al., Nature, 2009). In Asian population, only rs2958182 in the
TCF4 gene was reported an association with schizophrenia in Han
Chinese (p=3.64×10 -6 , Li et al., Biological Psychiatry, 2010).
Methodology: In the current study, we analyzed two SNPs,
rs2958182 and rs2924336 in 200 schizophrenia patients and sex- and
age-matched 200 normal control subjects, because rs9960767 in
Stefansson's report was not polymorphic in Japanese Hapmap data.
Selected two SNPs is located near rs9960767.
Results: The detailed result is shown at the congress.
69
PP4 TRANSCRIPTOMIC ANALYSIS OF POSTMORTEM
BRAIN IDENTIFIES DYSREGULATED SPLICE ISOFORMS
OF NOVEL CANDIDATE GENES FOR SCHIZOPHRENIA
O. Cohen*(1), S. Bialosuknia(1), M. Tsuang(2), F. Middleton (1), S.
Faraone(1), S. Glatt(1)
1. Psychiatric Genetic Epidemiology & Neurobiology Laboratory
(PsychGENe Lab) Departments of Psychiatry and Behavioral
Sciences SUNY Upstate Medical University 2. Center for Behavioral
Genomics Department of Psychiatry University of California, San
Diego
*coheno@upstate.edu
Introduction: The diverse expression of certain alternatively spliced
transcript variants contributes to the fine-tuning that controls
neurodevelopment. Alternative splicing, however, can be altered by
many different environmental and genetic variables and therefore,
result in unbalanced circuitry. Identifying dysregulated splice variants
in schizophrenia, which is known to have neurodevelopmental and
genetic origins, may shed light on the developmental mechanism(s)
of this disorder.
Methodology: Postmortem brain tissue samples were obtained from
20 individuals with schizophrenia (SZ) and 20 neuropsychiatrically
normal comparison subjects included in the Harvard Brain Tissue
Resource Center. Gray matter tissue samples were extracted from
two brain regions implicated in the disorder: Brodmann area 10
(BA10) and caudate head. Tissue from four subjects per group was
lysed, and total mRNA in each sample was isolated, reverse
transcribed, and hybridized to Affymetrix Human Gene 1.0 ST arrays
(exon array) to identify genes with dysregulated exons. Dysregulation
of exons identified on the exon array was confirmed by qPCR in each
of the eight tested subjects. Subsequent to confirmation, exons were
tested for replication in the remaining sample of 16 SZ and 16 (12
caudate) normal control tissues using the same primer sets.
Results: The exon array revealed numerous dysregulated exons and
genes of interest. Based on their profiles of exon dysregulation,
regional distribution, and involvement in neurodevelopment, two
genes were selected for further analysis, including the enabled
homolog of Drosophila (ENAH) and Kelch-like protein 5 (KLHL5).
Both genes are associated with cytoskeleton function, which
orchestrates dynamic aspects of cell activity such as axon guidance,
and cell migration, and are therefore attractive candidates in the study
of the pathological development that leads to SZ. In BA10 of SZ
brains, ENAH showed significantly lower exon 12 expression
(suggestive of its exclusion by alternative splicing) compared to
control brains by microarray however, ENAH exons were not
dysregulated in SZ in the caudate head. Analysis by qPCR confirmed
the exon-array results in both brain regions. Results were replicated
in BA10 while, contrary to the discovery sample, a significant
difference in exon 12 expression was observed in caudate head in the
larger replication sample. Exon 10 was found to be included in
KLHL5 isoforms more often in SZ than control in both BA10 and
caudate head. Confirmation and replication by qPCR showed the
same trend but were not significant in either brain region.
Conclusions: The differential exclusion or inclusion of specific
exons may result in different functions of the translated proteins. A
disturbance in the alternative splicing mechanism due to mutations in
the genes, malfunctioning alternative splicing regulators, or
environmental cues, may cause an imbalanced expression of isoforms
that, in turn, might contribute to the development of SZ.

PP5 ASSOCIATION STUDY AND EXPRESSION ANALYSIS
BETWEEN MAGI2 AND SCHIZOPHRENIA
T. Koide*(1,9), B. Aleksic(1,9), A. Yoshimi(2), I. Kushima(1,9), Y.
Nakamura(1,9), M. Ikeda(3), K. Ohi(4,9), Y. Yasuda(4,9), R.
Hashimoto(4,5,9), T. Inada(6), U. Hiroshi(7), M. Suzuki(8), M.
Takeda(4,5), N. Iwata(3,9), N. Ozaki(1,9)
1. Departments of Psychiatry, Nagoya University Graduate School of
Medicine 2. Departments of Neuropsychopharmacology and Hospital
Pharmacy 3. Department of Psychiatry, Fujita Health University
School of Medicine 4. Department of Psychiatry, Osaka University
Graduate School of Medicine 5. Molecular Research Center for
Children's Mental Development, United Graduate School of Child
Development, Osaka University, Kanazawa University, and
Hamamatsu University Graduate School of Medicine 6. Seiwa
Hospital, Institute of Neuropsychiatry 7. Ujike nishiguchi Clinic 8.
Department of Neuropsychiatry, University of Toyama 9. CREST,
Japan Science and Technology Agency
*t-koide@med.nagoya-u.ac.jp
Introduction: Schizophrenia is a complex, heritable psychiatric
disorder, affecting approximately 1% of the general population.
Although the heritability of schizophrenia was estimated to be about
64%, the genetic basis of schizophrenia is unclear. Recently, genes
related to schizophrenia or genetic variants that may modulate risk
for this disease have been identified using both linkage and candidate
based or whole genome association studies. The first schizophrenia
GWAS in the Japanese population known as homogeneous (JGWAS)
implied many associations in several loci, including the same SNPs
already reported in schizophrenia GWAS in the European population.
However, the sample size of JGWAS was relatively smaller (case
575 and control 564). Thus, the results of JGWAS should be
replicated in a larger independent population. From the possible
association signals of JGWAS, we selected membrane-associated
guanylate kinase, WW and PDZ domain-containing 2 gene (MAGI2)
region in terms of its biological evidence and strong intensity of
association signals. MAGI2 is located in 7q21 and ranging over about
1.44 mega base pairs. Linkage disequilibrium structure within the
MAGI2 locus is coarse with the multiple recombination hot spots.
MAGI2 interacts with ERBB4, which is related to NRG1 mediated
developmental signaling pathways. There was the only one
association study focusing on MAGI2 due to the gene length and LD
pattern. Therefore, in order to explore the association between
MAGI2 and schizophrenia, we conducted association study based on
locus signals implied in JGWAS within MAGI2 region and
expression analysis.
Methodology: Based on the result of first schizophrenia GWAS
(JGWAS) in Japanese population, known as homogeneous, we
selected 5 SNPs based on p-value from MAGI2 region and carried out
the association study using an independent large Japanese sample set
(case 1624, control 1621). To support our findings on genetic
association, we performed expression analysis of MAGI2 at mRNA
level in the sample consisted of lymphoblastoid cell lines derived
from 30 schizophrenic patients and the same number of age and
gender matched healthy controls.
Results: In the association study, using independent replication
sample we found trend for genetic association (best p=0.06), and
when the data are combined across two sample sets evidence for
association had strengthen (p=0.0033) by meta analysis using
PLINK. In the expression study, we couldn't observe significant
difference in expression between cases and controls.
Conclusions: Our results suggested possibility of genetic association
between common SNP within MAGI2 locus and schizophrenia in the
Japanese population. However, further studies involving larger
samples are needed.
70
PP6 WHOLE EXOME SEQUENCING REVEALS THE
GENETIC BASIS OF A CASE OF IDIOPATHIC HEMOLYTIC
ANEMIA AND SUGGESTS CANDIDATE RARE VARIANTS
FOR ADHD IN A UTAH PEDIGREE
G. Lyon*(1,3), T. Jiang(2), R. Robison(3), H. Hakonarson(1), M.
Yandell(3), R. VanWijk(5), L. Yang(2), P. Zhang(2), R. Wu(2), Y.
Liu(2), X. Yang(2), J. Xing(3), B. Moore(3), J. Glessner(1), W.
McMahon(3), K. Wang(4)
1. Center for Applied Genomics, CHOP 2. BGI-Shenzhen 3.
University of Utah 4. USC 5. University Medical Center Utrecht
*lyong1@email.chop.edu
Introduction: Exome sequencing has identified the causes of several
Mendelian diseases, although it has rarely been used in a clinical
setting to diagnose the genetic cause of a disorder in a single patient.
Methodology: Exome capture was carried out using a commercially
available Agilent SureSelect in solution method as per the
manufacturer guidelines. Each captured library was loaded on the
Illumina GAIIx platform, and GA sequencing was performed for
each captured library independently to ensure each sample had at
least 20x coverage on the exome. Variants are functionally annotated
using the ANNOVAR software using a SIFT cutoff of 0.05 and the
allele frequency measure from the 1000 Genomes Project.
Additionally, the variants reduction pipeline, with some differences
for recessive model and dominant model, was utilized in trimming
down the potential functional candidates.
Results: We performed exome sequencing on a pedigree with a
father and two sons with attention deficit/hyperactivity disorder
(ADHD), to identify candidate genes for this complex disease. Over
the course of the study, one subject was discovered to have an
idiopathic hemolytic anemia (IHA) with subsequent spleen removal,
which was suspected to be genetic in origin. Analysis of his exome
readily identified him to be a compound heterozygote for two rare
non-synonymous mutations in PKLR, likely causing the IHA. We
confirmed the deficiency by functional biochemical testing,
consistent with a diagnosis of red blood cell pyruvate kinase
deficiency. Using a new software program (VAAST) developed by
Mark Yandell at the University of Utah, we prioritized many
candidate variants that might be causative for the ADHD in this
family. We are studying these variants in case-control cohorts and
other pedigrees, along with conducting functional studies.
Conclusions: We present our results explaining the cause of
idiopathic hemolytic anemia, along with many possible candidate
rare variants that could be causative for ADHD. Our study has
clinical and ethical implications for exome sequencing in a research
setting. How to handle unrelated findings of clinical significance in
the context of originally planned complex disease research remains a
largely uncharted area for clinicians and researchers. We specifically
discuss our experience with this dilemma and offer our views on how
to make the most out of exome sequencing data.

PP7 POSTMORTEM HIPPOCAMPAL GABAERGIC GENE
EXPRESSION IN ALCOHOLICS AND COCAINE ADDICTS:
TRANSLATIONAL FINDINGS IN ALCOHOL NAIVE P AND
NP RATS
M. Enoch*(1), Z. Zhou(1), M. Kimura(1), D. Mash(2), Q. Yuan(1),
D. Goldman(1)
1. NIAAA, NIH 2. University of Miami School of Medicine
*maenoch@niaaa.nih.gov
Introduction: Addiction to alcohol and cocaine results in neuronal
adaptation. Equally, neurobiological variation, for example in the
GABAergic system that is strongly implicated in the acute and
chronic effects of alcohol, may predispose to the development of
addiction. In this study we attempted to distinguish between trait and
state effects using a translational approach by comparing the relative
expression of GABAergic genes in postmortem hippocampus of
alcoholics, cocaine addicts and controls and in postmortem
hippocampus of alcohol naïve P and NP rats, selectively bred for
extremes of alcohol seeking behavior.
Methodology: Samples of postmortem hippocampus were obtained
from the University
of Miami Brain Endowment Bank from 8
alcoholics, 8 cocaine addicts and 8 controls, all men. There were no
group differences in mean age, ethnicity or postmortem interval.
Total RNA was extracted, mRNA was isolated and high-throughput
parallel sequencing was performed across the whole genome using
the Illumina Genome Analyzer. Approximately 346 million bases
were mapped per sample. The read counts were then log2
transformed and normalized using quantile normalization before
group comparisons were performed. Selectively bred alcoholpreferring
(P) and non-preferring (NP) male rats, 8 in each group, all
sacrificed at 90 days, were obtained from the Indiana University
School of Medicine. The identical RNA Seq method was used to
perform whole genome sequencing of mRNA transcripts. Following
global analyses of the 16,008 genes in humans and 11,406 genes in
rats that had identifiable transcripts in the hippocampus we then
focused on 25 candidate genes that encode proteins implicated in
GABA synthesis, metabolism, synaptic transmission and re-uptake.
Results: In human hippocampus there were both common and
specific effects in GABAergic pathway genes. In both cocaine
addicts and alcoholics, genes encoding GAT1 (GABA transporter)
and GABBR1 (presynaptic autoreceptor) were down-regulated,
potentially resulting in increased GABA in the synaptic cleft.
GABRG2, encoding the gamma2 subunit, a component of nearly all
GABA A postsynaptic receptors, was downregulated in both
alcoholics and cocaine addicts. GABRA2 and GABRG1 were only
down-regulated in alcoholics, mirroring the strong associations with
alcoholism in case-control studies in humans. Cocaine addicts had
reduced expression of genes implicated in GABA synthesis. Robust,
overlapping findings between alcoholics, cocaine addicts and P rats
included changes in expression of GABBR1 and GABRG2 and genes
encoding GABA A receptor-associated trafficking proteins.
Conclusions: Our study has demonstrated that, at least within the
hippocampus, chronic alcohol and cocaine exposure results in both
common and specific changes in expression of GABAergic genes
that are directionally consistent and biologically plausible. In
particular, the key finding of significant down-regulation of
GABBR1 in alcoholics, cocaine addicts and alcohol naïve P rats
indicates that down-regulation of this gene that encodes GABAB
receptors, potentially resulting in increased GABA in the synaptic
cleft, may be a risk factor for the development of addiction in
humans. Indeed, preclinical studies have shown that activation of
GABAB receptors blocks the rewarding effects of drugs of abuse.
Our findings may therefore have possible therapeutic potential.
71
PP8 ASSOCIATION OF TPH2 GENE WITH SUICIDAL
BEHAVIOR IN THE CHINESE POPULATION
B. Liu(1,2,3), S. Chen(1,2,3), X. Li(1,2,3), Y. Wang(1,2,3), Q.
Zhao(1,2,3), X. Li(1,2,3), Q. Shen(1,2,3), L. He(1,2,3), G. He*(1,2,3)
1. Bio-X Center, Key Laboratory for the Genetics of Developmental
and Neuropsychiatric Disorders (Ministry of Education), Shanghai
Jiao Tong University 2. Institutes of Biomedical Sciences, Fudan
University, 138 Yixueyuan Road 3. Institute for Nutritional Sciences,
Shanghai Institutes of Biological Sciences, Chinese Academy of
Sciences, 320 Yueyang Road
*heguang@sjtu.edu.cn
Introduction: Suicidal behavior (SB) has been a devastating and
challenging worldwide public-health problem. SB is the fifth leading
cause of overall death and the primary cause of adolescent death in
China. Evidence from family, twin, and adoption studies does suggest
that genetic factors might be involved in the etiology of SB. The
TPH2 gene, located on 12q21.1, is crucial for brain serotonin
synthesis and predominantly expressed in the brain stem. In order to
clarify the role of TPH2 gene in Chinese SB, we undertook an
association study of this gene with Chinese subjects. Our results
support that TPH2 gene may contribute to the etiology of SB.
Methodology: Six polymorphisms of TPH2 Gene (rs10784941,
rs1386494, rs2171363, rs476816, rs1386486, and rs1872824) were
tested in a total of 297 suicide attempt patients (SA) (126 female, age
46.10±13.14 years) and 329 non-suicide attempt patients (NSA) (112
female, age 43.22±12.27 years), 67% of SA experienced at least once
violent suicide. All the samples were Han Chinese in origin from
Shanghai. Diagnostic and Statistical Manual of Mental Disorder,
Third Revised Edition (DSM-III-R), was taken as the diagnosis
criteria. Each subject was given a standardized interview and
diagnosis was confirmed by clinical interviews conducted by at least
two independent experienced psychiatrists. Written informed consent
was obtained from either the participants or the participants' legal
representatives after the research aims and procedures were fully
explained. The study protocol was reviewed and approved by the
Shanghai Ethical Committee of Human Genetic Resources.
Peripheral blood samples for DNA extraction were obtained from the
subjects with the classical phenol-chloroform method.
Results: Between 297 SA and 329 NSA individuals, SNP
rs10784941 showed statistically difference in both allele frequencies
(p=0.0259, OR=0.76, 95% CI [0.60-0.97]) and genotype frequencies
(p=0.0169). Visibly, the frequency of G allele is higher in SA (45.4
%) than that in NSA (38.8%). SNP rs4760816 exhibited difference in
only allele frequencies (p=0.0291, OR=0.77, 95%CI [0.61-0.97]).
Haplotype "GCGTAA" is more prevalent in SA than in NSA, which
accounted for 9.2% and 4.1% respectively, and showed the
significant difference between SA and NSA (p=0.001, OR=2.35,
95%CI [1.38-4.01]).
Conclusions: Both the single point and multi-locus haplotype
analysis strongly support that TPH2 may be a susceptibility gene for
SB in Chinese. In conclusion, our results forcefully support that
TPH2 may be an important gene in the predisposition to SB.

PP9 ASSOCIATION STUDY OF NEUROTROPHIC
FACTORS AND RECEPTORS GENES WITH SERUM BDNF
A. Terracciano*(1), M. Piras(2), M. Lobina(2), O. Meirelles(1), A.
Mulas(2), W. Chan(1), A. Sutin(1), L. Crisponi(2), D.
Schlessinger(1)
1. National Institute on Aging NIH 2. Istituto di Ricerca Genetica e
Biomedica, CNR
*terraccianoa@mail.nih.gov
Introduction: The purpose of this research is to identify genetic
variants associated with levels of Brain Derived Neurotrophic Factor
(BDNF) in serum. BDNF plays a key role in the survival, growth,
and differentiation of neurons. Levels of BDNF in serum are lower in
mood disorder patients and increase in response to antidepressant
treatment. Lower serum BDNF is also found in subjects scoring high
on neuroticism, a stable tendency to experience negative emotions
and a predisposing factor for mood disorders.This study estimates the
heritability of serum BDNF and investigates whether SNPs in genes
encoding neurotrophic factors and their receptors are associated with
serum BDNF. We examine the BDNF Val66Met functional variant,
which has been investigated in previous studies with mixed results
(Cattaneo et al., 2010, Jiang et al., 2009, Lang et al., 2009, Minelli et
al., in press, Ozan et al., 2010, Terracciano et al., 2010a, Trajkovska
et al., 2007). In addition, we test for associations between serum
BDNF and SNPs in four neurotrophic factor genes (NGF,
BDNF,NTF3, and NTF4) and their receptors (NTRK1, NTRK2,
NTRK3, and NGFR).
Methodology: We performed the association test on a family-based
sample (N = 2054) from Sardinia, Italy. We measured serum BDNF
concentration and conducted a genome-wide association scan
(GWAS).
Results: From a set of 428 sib-pairs, one pair from each nuclear
family with available data, we estimated a heritability of 0.48 for
serum BDNF.There was no association between serum BDNF and
Val66Met (rs6265 p > 0.05). A meta-analysis that combined the
current and published studies also found no association between
peripheral levels of BDNF and the BDNF Val66Met variant. The
analyses of SNPs from 8 genes encoding neurotrophic factors and
their receptors identified several SNPs with nominally significant
associations, including SNPs in the BDNF gene (e.g., rs11030102, p
= .001). The strongest effect was found for the genotyped SNP
rs7170215 (P = 4.8x10 -5 ), which maps within the neurotrophic
tyrosine kinase receptor, type 3 (NTRK3). The A allele (frequency
56%) was associated with lower serum BDNF concentrations (Beta =
-0.51, SE = 0.13), an effect that explained approximately 1% of the
variance in serum BDNF. An additional association signal was
present at the 5' of NTRK3, with rs11073742 (P = 1.2x10 -5 T allele:
frequency 65%, Beta = -0.56, SE = 0.13).
Conclusions: NTRK3 is a neurotrophic receptor that mediates the
neurotrophic/TRK signal transduction pathway. This finding suggests
that NTRK3 receptor might play a role in regulative feedback on the
expression and storage of BDNF. This gene has also been proposed
as a candidate gene for a number of psychiatric disorders, including
major depressive disorder (Feng et al., 2008, Verma et al., 2008) and
bipolar disorder (Athanasiu et al.). In conclusion, our study and a
meta-analysis of the literature indicate that the BDNF Val66Met
variant is not associated with serum BDNF. Our study further
indicates that a common variant in NTRK3 might regulate the level of
BDNF in serum, one of the best characterized biomarker of mood
disorders.
Acknowledgments: This research was supported in part by the
Intramural Research Program of the NIH, National Institute on
Aging.
72
PP10 ASSOCIATION BETWEEN NEGATIVE MOOD
DELUSIONS IN BIPOLAR DISORDER AND GENETIC
VARIATIONS IN 3Q26.1
ECIP
S. Meier*(1), J. Treutlein(1), J. Frank(1), J. Strohmaier(1), R.
Breuer(1), C. Schmäl(1), E. Vassos(2), M. Mattheisen(3,4,5), F.
Degenhardt(3,4), T. Mühleisen(3,4), B. Hänisch(3,4), L. Priebe(3,4),
T. Schulze(6), M. Nöthen(3,4), S. Cichon(3,7), M. Rietschel(1)
1. Department of Genetic Epidemiology in Psychiatry, Central
Institute of Mental Health, University of Heidelberg 2. Social,
Genetic and Developmental Psychiatry Centre, Institute of
Psychiatry, King's College London 3. Department of Genomics, Life
& Brain Center, University of Bonn 4. Institute of Human Genetics,
University of Bonn 5. Institute for Medical Biometry, Informatics,
and Epidemiology, University of Bonn 6. Department of Psychiatry
and Psychotherapy, University Medical Center, Georg-August-
University 7. Institute of Neuroscience and Medicine (INM-1),
Research Center Juelich
*sandra.meier@zi-mannheim.de
Introduction: It has previously been suggested that clinical symptom
dimensions in bipolar disorder (BD) may prove more useful for
delineating the genetics of the disorder than standard diagnostic
models. This concept, however, has not yet been applied to data from
genome-wide association studies (GWAS) in BD.
Methodology: We performed a GWAS of factor dimensions in 637
clinically well-characterized BD patients all of German ancestry. In a
subsequent follow-up study of our top GWAS results, we included an
additional 290 BD patients of German ancestry.
Results: Rs9875793 located in an intergenic region on 3q26.1was
significantly associated with the factor dimension Negative Mood
Delusions in the combined BD sample (n= 927 P= 4.65 x 10 -8 , OR=
2.66). In a subsequent case-control analysis the G allele of rs9875793
in was overrepresented in patients with Negative Mood Delusions
symptoms (P= 0.0007, OR= 1.74), currently we aim to replicate this
finding in an independent sample of BD patients. Further we
explored whether the association of rs9875793 with Negative Mood
Delusions can be extended to patients with schizophrenia and major
depression disorder (MDD) (n=554) and (SCZ) (n= 977). We
observed a trend for association of rs9875793 with Negative Mood
Delusions in MDD patients, and allele frequencies of rs9875793
differentiated schizoaffective patients of depressive subtype from
other SCZ patients.
Conclusions: In summary,we have demonstrated that refining
phenotypes in genetic associations studies can facilitate the search for
more valid nosological entities. Further our results suggested that the
association of the chromosome 3 variant rs9875793 with a specific
clinical symptom pattern compiled of negative mood and delusions is
observable across diagnostic borders.

PP11 EXPRESSION DATA FROM MULTIPLE BRAIN
REGIONS AND POLYGENIC SCORE ANALYSIS
A. Richards*, L. Jones, P. Holmans, M. O'Donovan
Cardiff University
*wmdalr@cf.ac.uk
Introduction: Variation in gene expression is a possible mechanism
by which genetic polymorphisms may confer susceptibility to
schizophrenia. The International Schizophrenia Consortium (ISC)
found that schizophrenia risk alleles are enriched among SNPs
selected for marginal evidence for association (p < 0.5) from genome
wide association analyses. We have previously demonstrated that
marginally associated alleles with a greater effect on brain gene
expression are superior predictors of schizophrenia affected status
through polygenic score analysis than those with a lesser effect. Here,
we examine whether using gene expression data from multiple brain
areas can further enhance this prediction.
Methodology: We used an eQTL dataset containing 163 adult
control samples, each with data for four brain regions (frontal and
temporal cortices, pons and cerebellum). We assigned high or low
eQTL status to SNPs separately for each brain region, and also based
upon a combination of the four regions. SNPs associated (p < 0.5)
with schizophrenia status were then identified using the large PGC
meta-analysis of schizophrenia GWAS studies, excluding the ISC
dataset. The high eQTL and low eQTL SNP sets were then used to
predict schizophrenia disease status of samples in the ISC GWAS
dataset using the polygenic score method of analysis reported by the
ISC.
Results: We observed that higher probability cis-eQTLs predicted
schizophrenia status significantly better in independent datasets than
those with a lower probability for being a cis-eQTL. This effect
became several orders of magnitude more significant when eQTL
data based upon a combination of brain regions was used (p=7.5e -7 ).
Conclusions: These results further support our hypothesis that some
schizophrenia risk alleles affect the progress of the disorder via their
effects on expression with a high level of statistical significance.
They also demonstrate the utility of combining expression data from
multiple brain regions.
73
PP12 A GENOME WIDE SURVEY SUPPORTS THE
INVOLVEMENT OF LARGE COPY NUMBER VARIANTS IN
MENTAL RETARDATION AND SCHIZOPHRENIA
E. Derks*(1), S. MacGregor(2), A. Maclean(3), A. McKechanie(3),
A. McRae(2), B. Pickard(4), S. Purcell(5), P. Sklar(5), D. StCLair(6),
N. Wray(2), P. Visscher(2), D. Blackwood (3)
1. University Medical Center Utrecht 2. Queensland Institute of
Medical Research 3. University of Edinburgh 4. University of
Strathclyde 5. Center for Human Genetic Research 6. Aberdeen
University
*e.m.derks@umcutrecht.nl
Introduction: Mental retardation is associated with high rates of
psychiatric disorders (e.g., schizophrenia, autism). Previous studies
have shown increased rates of Copy Number Variants (CNVs) both
for mental retardation and psychiatric disorders with large overlap in
candidate regions. The aim of this study is to study the role of large
(>100 kb and >1Mb) CNVs in a sample of 170 Scottish patients with
mental retardation.
Methodology: Samples were genotyped using the Affymetrix 6.0
array.A psychiatric condition was present in 119 subjects, including
schizophrenia (N=64), autism (N=19), bipolar disorder (N=21), and
depression (N=15) as primary diagnoses. Subjects were divided into
two groups: subjects with mental retardation and a clinical diagnosis
for schizophrenia (MR+SCZ N=64), and subjects with mental
retardation and no clinical diagnosis except for depression (MR only
N=66).We selected only those CNVs with a LOD>10 and physical
length greater than 100 kb and restricted analysis to the remaining
1,791 segments.
Results: Including all CNVs larger than 100kb, CNV burden (total,
deletions, and duplications) was similar in “MR+SCZ” and “MR
only”. Restricting analysis to CNVs larger than 1Mb, total CNV
burden was higher in “MR+SCZ” (rate=.25) compared to “MR only”
(rate=.09 empirical p=.03) which was mainly explained by an
increased number of large duplications (rates are .16 and .02,
respectively, empirical p=.01). Seven of the 33 large CNVs were
located at candidate regions 1q21.1, 15q13.1, 16p13.1, and 22q11.21
which is a significant enrichment of the candidate regions (p=.002).
Of the 26 CNVs located outside candidate regions, ten CNVs (9
schizophrenia patients and 1 bipolar patient) were located at 15q11.2
(18.5-20.1Mb). This region does not overlap with the previously
reported candidate region at 15q11.2 (20.3-20.8Mb). The CNV
burden in this region is significantly higher in “MR+SCZ” subjects
(rate=.14) compared to “MR only” subjects (rate=0.0 empirical
p=.001). The finding was replicated in the Scottish International
Schizophrenia Consortium (ISC) samples as we detected a higher
CNV rate in 1130 schizophrenia cases (rate=.088) compared to 984
controls (rate=.066 Empirical p=.038).
Conclusions: The CNV burden for large (>1Mb) CNVs is increased
in patients with mental retardation and schizophrenia compared to
patients with mental retardation only. Furthermore, candidate regions
for neurodevelopmental disorders are significantly enriched for
CNVs larger than 1Mb. We replicated the role of CNVs in regions
1q21.1, 15q13.1, 16p13.1, and 22q11.21 in causing mental
retardation with or without psychiatric diagnosis and in addition
identified a novel region of interest for schizophrenia. This region is
located at chromosome 15q11.2 (18.5 to 20.1Mb) and includes the
POTEB (POTE ankyrin domain family, member B) gene. The
function of this gene might be related to the function of ANK3
(ankyrin 3, node of Ranvier) which has been found to be associated
with bipolar disorder.

PP13 INVESTIGATING THE CONTRIBUTION OF
COMMON GENETIC VARIANTS TO THE RISK AND
PATHOGENESIS OF ADHD
E. Stergiakouli*(1), M. Hamshere(1), P. Holmans(1), K. Langley(1),
I. Zaharieva(1), A. Pocklington(1), Z. Hawi(2), L. Kent(3), M.
Gill(2), N. Williams(1), M. Owen(1), M. O'Donovan(1), A.
Thapar(1)
1. MRC Centre in Neuropsychiatric Genetics and Genomics, Cardiff
University 2. Department of Psychiatry, Trinity Centre for Health
Sciences 3. Bute Medical School
*stergiakoulie@cardiff.ac.uk
Introduction: Although rare copy number variants (CNVs) appear to
contribute to ADHD, the role of common risk variants (SNPs) in
ADHD is still unclear. However, ADHD GWAS have not been
adequately powered up to date. In our study, we performed a GWAS
of ADHD with the aim being to identify associated variants and also
examine whether SNPs, including those below conventional levels of
significance, impact on the same biological pathways hit by CNVs.
Methodology: 727 children with ADHD and 5,081 controls were
analysed using Illumina arrays. Single locus tests were performed as
well as ALIGATOR pathway analysis (Holmans et al. 2009) on a
large set of pathways from a variety of public databases. The gene
sets enriched in pathway analysis of our GWAS data were tested for
an excess of genes hit by large, rare CNVs (>500kb,

PP15 WHOLE GENOME ASSOCIATION SCAN OF HIGH
RESOLUTION REGIONAL MRI VOLUME AND THICKNESS
MEASURES FOR LINKING GENETICS OF BRAIN
CHANGES WITH ALZHEIMER'S DISEASE
M. Khondoker*
*mizanur.khondoker@kcl.ac.uk
Introduction: Genome-wide association studies has been an
effective tool for understanding the genetic basis of many complex
diseases. However, apart from the APOE, comparatively little is
known about the contribution of genetic risk alleles to Alzheimer's
disease (AD). APOE ε 4 allele accounts for only a tiny fraction of the
heritability of AD and many more genetic risk alleles are thought to
be undiscovered. Imaging genetics, where associations between
quantitative brain imaging measures and genetic variants are
investigated, has recently emerged as an interesting research area for
linking genetics of brain changes with AD.
Methodology: In this study, we undertake a genome wide association
scan of high resolution whole brain automated magnetic resonance
imaging (MRI) regional cortical volume and thickness measures
combining the genetics and imaging data obtained from the
Alzheimer's Neuroimaging Initiative and the AddNeuroMed study.
Results: Imaging genetics analysis has been done previously with a
lower coverage of the brain image (e.g., only AD-related brain
region). In the current analysis with a better coverage of the whole
brain image and bigger sample size, we anticipate to detect novel
genetic susceptivity loci for AD.
Conclusions: Imaging genetics analysis has been done previously
with a lower coverage of the brain image (e.g., only AD-related brain
region). In the current analysis with a better coverage of the whole
brain image and bigger sample size, we anticipate to detect novel
genetic susceptivity loci for AD.
75
PP16 RESEQUENCING AND FOLLOW-UP OF VAV3
GUANINE NUCLEOTIDE EXCHANGE FACTOR IN
SCHIZOPHRENIC PATIENTS
B. Aleksic(1), I. Kushima(1), M. Ikeda(2), A. Yoshimi(1), H.
Ujike(3), M. Suzuki(4), T. Inada(5), M. Takeda(6), K. Kaibuchi(7),
N. Iwata(2), N. Ozaki(1)
1. Department of Psychiatry, Nagoya University Graduate School of
Medicine 2. Department of Psychiatry, Fujita Health University
School of Medicine 3. Department of Neuropsychiatry, Okayama
University Graduate School of Medicine, Dentistry and
Pharmaceutical Sciences 4. Department of Neuropsychiatry,
University of Toyama Graduate School of Medicine and
Pharmaceutical Sciences 5. Seiwa Hospital, Institute of
Neuropsychiatry 6. Department of Psychiatry, Osaka University
Graduate School of Medicine 7. Department of Cell Pharmacology,
Nagoya University Graduate School of Medicine
Introduction: In recently completed Japanese genome wide
associated study of schizophrenia one of the top association signals
(within top 10 hits) was detected in the region of VAV3, a gene that
maps to the chromosome 1p13.3. To follow-up this association
signal, we performed resequencing of VAV3 and evaluated effect of
associated common variant on expression pattern of VAV3.
Methodology: Four independent samples were used in the present
study: (1) 575 unrelated patients with schizophrenia and 564 subjects
with no personal or family history of psychiatric disorders were
selected for genome wide screening analysis, (2) for the replication
analysis we used sample comprising 1511 cases and 1517 healthy
controls (3) mutation analysis was performed on a total of 321
patients suffering from schizophrenia and (4) Lymphoblastoid cell
lines sample derived from 30 schizophrenic patients and same
number age and gender matched healthy controls was used for
expression analysis. As basis for a more detailed functional
interpretation of the novel rare variants, we performed ab-initio
structure predictions and comprehensive in-silico analysis.
Results: Four rare novel missense variants were detected in the
present study. The mutations were followed-up in large independent
case controls sample (>4000 subjects) and one of the novel variants
was associated with schizophrenia. Moreover, three different
bioinformatics algorithms had predicted functional effect of rare
variant that was associated with schizophrenia. We couldn't detect
that expression of VAV3 is influenced by associated common variant.
Conclusions: We conclude that these results are suggestive of an
association with schizophrenia at VAV3 locus, but that they could
not be considered conclusive without further replications.

PP17 DEEP RESEQUENCING AND ASSOCIATION
ANALYSIS OF SCHIZOPHRENIA CANDIDATE GENES
P. Sullivan(1), C. Hilliard*(1), J. Crowley(1), Y. Kim(1), M.
Morgan(2), P. Sklar(3), S. Purcell(3,4), J. Lieberman(5), R. Gibbs(2)
1. Departments of Genetics, University of North Carolina 2. Human
Genome Sequencing Center and Department of Molecular and
Human Genetics, Baylor College of Medicine 3. Center for Human
Genetic Research, Massachusetts General Hospital 4. The Broad
Institute of Harvard and MIT 5. Department of Psychiatry, Columbia
University
*chillia@email.unc.edu
Introduction: In 2006, there were ~10 genes for which there was
reasonable evidence for involvement in the etiology of schizophrenia
(COMT, DAOA, DISC1, DRD2, DRD3, DTNBP1, HTR2A, NRG1,
SLC6A3, SLC6A4). The pattern of results for these genes suggests
that there may be sequence variants that have not yet been
discovered, and re-sequencing has been limited.
Methodology: To address this limitation, we re-sequenced the
coding regions, 5-prime and 3-prime UTRs, splice sites, promoters
and conserved intronic regions of these 10 genes in 727 cases with
schizophrenia from the CATIE clinical trial and 729 matched
controls.
Results: A total of 778 single nucleotide polymorphisms (SNPs)
were identified by Sanger re-sequencing, including 620 novel
variants. DISC1 showed a significantly enriched total SNP count
relative to controls and relative to the other nine genes, primarily in
the form of novel non-synonomous variants. A total of 92 high
priority variants were deemed worthy of genotyping in a larger
population, based on a combination of factors including: association
with schizophrenia in CATIE, novelty, SNP type (non-sense and
missense mutations) and minor allele frequency in cases of European
ancestry. These 92 variants have now been genotyped in an
independent sample of 3,391 schizophrenia cases and 3,181 controls,
all of European ancestry, a subset of the International Schizophrenia
Consortium (ISC). Analyses examining association of these variants
with schizophrenia are now being finalized.
Conclusions: These data are expected to provide a clearer picture of
the role that variation in traditional candidate genes plays in
schizophrenia etiology.
76
PP18 SUPPORT FOR INVOLVEMENT OF GLUTAMATE
DECARBOXYLASE 1 AND NEUROPEPTIDE Y IN ANXIETY
DISORDER SUSCEPTIBILITY
J. Donner(1,2,3), T. Sipilä(1,2,3), S. Ripatti(4), L. Kananen(1,2), J.
Lönnqvist(3,5), S. Pirkola(5), I. Hovatta*(1,2,3,4)
1. Research Programs Unit, Molecular Neurology, Biomedicum-
Helsinki, University of Helsinki 2. Department of Medical Genetics,
Haartman Institute, University of Helsinki 3. Department of Mental
Health and Substance Abuse Services, National Institute for Health
and Welfare 4. Institute of Molecular Medicine Finland (FIMM),
University of Helsinki 5. Department of Psychiatry, Helsinki
University Central Hospital
*iiris.hovatta@helsinki.fi
Introduction: Anxiety disorders, including panic disorder,
generalized anxiety disorder, obsessive-compulsive disorder, posttraumatic
stress disorder, and phobias, are one of the most common
mental illnesses characterized by excessive, prolonged and
debilitating levels of anxiety. Their onset is influenced by both
genetic and environmental factors, with heritability estimates
averaging 30-40 %. Given the small effect sizes of risk genotypes
indentified in anxiety disorders, it has become increasingly apparent
that understanding of interplay between genetic and environmental
factors is needed to better explain the underlying etiology.
Methodology: We carried out a genetic association analysis of two
genes previously implicated in anxiety susceptibility, glutamate
decarboxylase 1 (GAD1), and neuropeptide Y (NPY). Our sample
consisted of the Finnish population-based Health 2000 sample
including 282 anxiety disorder cases and 575 matched controls. We
first tested 8 single nucleotide polymorphisms (SNPs) from GAD1
and 10 from NPY for association to anxiety disorders. Second, we
examined the interaction of these SNPs and the number of childhood
adverse life events, one the strongest known risk factors for anxiety
disorders, on the development of the anxiety disorder.
Results: In a subgroup of patients with phobias, we observed
evidence for association to GAD1 (P = 0.0001). In addition, we found
that individuals having experienced more childhood adverse life
events had a greater risk of developing an anxiety disorder if they
carried specific risk genotypes within the NPY locus (P = 0.004).
Conclusions: Genetic variation in GAD1 and NPY may affect
susceptibility to anxiety disorders in the Finnish population. The
effect of NPY was only seen in an interaction with childhood adverse
life events. This finding highlights the importance of environmental
risk factors in influencing predisposition to anxiety disorders.

PP19 INVESTIGATION OF THE INVOLVEMENT OF DE
NOVO CODING POINT MUTATIONS IN EHMT1 IN
SCHIZOPHRENIA
S. Dwyer*, G. Kirov, M. Owen, M. O'Donovan
MRC Centre in Neuropsychiatric Genetics and Genomics,
Department of Psychological Medicine and Neurology, Cardiff
University School of Medicine
*dwyersl@cf.ac.uk
Introduction: In the largest study of de novo copy number variants
in schizophrenia to date, we found 2 de novo CNVs that disrupt
EHMT1 (presented at this meeting). EHMT1 encodes for
euchromatin histone methyltransferase which is involved in
epigenetic regulation through histone methylation. A recent study
has shown that EHMT is a key epigenetic regulator of neuronal genes
and processes which regulate simple learning and complex memory
in Drosophila (Kramer et al 2011). CNVs and point mutations at this
locus are known to cause 9q subtelomere deletion syndrome (9qSDs),
a neurodevelopmental disorder that is characterised by severe mental
retardation and hypotonia. Behavioural problems have also been
reported in a proportion of 9qSDs cases (Stewart et al 2007). Given
that de novo CNVs at EHMT1 have been shown to occur in a small
proportion of patients with schizophrenia, the aim of this study was to
identify if de novo coding point mutations exist at the same locus in
690 cases.
Methodology: The sample used consisted of 690 parent-proband
trios with schizophrenia from Bulgaria. A total of 29 fragments
which encompassed the coding region of EHMT1 were screened in
the probands using the LightScanner and Sanger sequencing. The
parents of individuals harbouring rare coding mutations were
subsequently sequenced to assess whether variants were de novo. The
possible effects of the variants on the protein and exon splicing was
determined using PolyPhen, SIFT and SKIPPY.
Results: We did not find any de novo point mutations in our sample.
We did find several mutations predicted to be damaging, 4 of which
occurred in multiple individuals
Conclusions: Within the constraints of sample size, we find no
evidence that de novo point mutations at EHMT1 occur in probands
with schizophrenia. We are currently sequencing the gene in a set of
control probands to test whether rare transmitted damaging mutations
occur at an increased rate in people with schizophrenia.
77
PP20 NEXT GENERATION SEQUENCING ANALYSIS OF
SPLICING PATTERNS AND EXONIC VARIATION IN THE
SCHIZOPHRENIA CANDIDATE GENE DPYSL2
C. Winchester*(1,3,4), G. Hamilton(2), B. Morris(1,3), J. Pratt(1,4),
R. Hunter(1,5), M. Bailey(6)
1. Psychiatric Research Institute of Neuroscience in Glasgow
(PsyRING), Universities of Glasgow and Strathclyde 2. Institute of
Molecular, Cell and Systems Biology, College of Medical,
Veterinary and Life Sciences, University of Glasgow 3. Institute of
Neuroscience and Psychology, College of Medical, Veterinary and
Life Sciences, University of Glasgow 4. Strathclyde Institute of
Pharmacy and Biomedical Sciences, Centre for Neuroscience
University of Strathclyde (CeNsUS), University of Strathclyde 5.
Gartnavel Royal Hospital 6. School of Life Sciences, College of
Medical, Veterinary and Life Sciences, University of Glasgow
*catherine.winchester@glasgow.ac.uk
Introduction: Next generation sequencing is a powerful
technologyrevolutionising our analysis and understanding of
genomes. It is particularly useful for deep re-sequencing of the
human genome to elucidate the genetic basis of complex polygenic
disorders such as schizophrenia that arise from influences of multiple
common and rare variants in many genes. Dihydropyrimidinase-like
2 (DPYSL2) is an emerging candidate risk gene for the disorder. We
and others have shown association of DPYSL2 gene variants with
schizophrenia in case-control association studies and our data show
that DPYSL2 transcripts are differentially expressed in the prefrontal
cortex from schizophrenia patients and from a rodent PCP model of
cognitive deficits and that DPYSL2 SNP alleles have effects on
DPYSL2 transcript expression. Recently it emerged that differential
expression of DPYSL2 protein in brain regions with clinical
relevance to schizophrenia is one of the most reproducible findings
across proteomic studies.
Methodology: DPYSL2 transcripts were sequenced from overlapping
RT-PCR products generated from RNA isolated from the prefrontal
cortex of 36 schizophrenia patients and healthy controls (n=18).
Indexed libraries were generated from each sample and paired-end
sequencing was performed on the Illumina Genome Analyzer II. The
data underwent quality control measures using an automated pipeline,
then were aligned to the reference genome sequence using TOPHAT
and further analysed using custom scripts. Exonic variants were
identified usingBCFTools andVCFTools. Splice site variation was
identified by custom scripts and visualised in the UCSC Genome
Browser.
Results: This approach resulted in a massive depth of nucleotide
coverage (>10,000x) with approximately 500,000 reads of 85
nucleotides per sample, enabling confidence estimates to be made for
any findings that differed from the reference sequence. We have
identified, several novel coding variants, alternate splicing patterns at
the 5' end of the gene and novel transcript isoforms with skipped
exons.
Conclusions: Next generation sequencing for deep re-sequencing is
facilitating the elucidation of the genetic basis of schizophrenia by
identifying novel common and rare variants in schizophrenia risk
genes. We demonstrate the utility of this approach with DPYSL2.

PP21 A GENOME-WIDE ASSOCIATION STUDY AND
FOLLOW-UP ANALYSIS OF DANISH SCHIZOPHRENIA
CASES AND CONTROLS
D. Demontis*(1), J. Pallesen(1), J. Grove(1), C. Pedersen(2), M.
Hollegaard(3), A. Hedemand(1), M. Nordentoft(4), M.
Mattheisen(5), S. Cichon(5), G. Consortium(1,5), S. Steinberg(6), H.
Stefansson(6), D. Hougaard(3), P. Mortensen(2), O. Mors(7), A.
Børglum(1,7)
1. Institute of Biomedicine, Dept. of Human Genetics, Aarhus
University 2. National Centre for Register-based Research, Aarhus
University 3. Dept. of Clinical Biochemistry and Immunology,
Section of Neonatal Screening and Hormones, Statens Serum Institut
4. Psychiatric Centre Copenhagen, Copenhagen University Hospital
5. Institute of Human Genetics, University of Bonn 6. deCODE
Genetics 7. Centre for Psychiatric Research, Aarhus University
Hospital
*ditte@humgen.au.dk
Introduction: In order to investigate genetic risk variants implicated
with schizophrenia in the Danish population we have performed a
genome-wide association study of cases and controls all born in
Denmark (stage 1) and subsequently genotyped the most significantly
associated SNPs in a follow up sample (stage 2).
Methodology: Stage 1: The investigated sample consisted of cases
diagnosed with schizophrenia according to ICD-10 and controls all
obtained from the Danish Newborn Screening Biobank. DNA was
extracted from dried blood spots and each sample was wholegenome-amplified
in three separate reactions which were pooled
before genotyping on the Illumina Human 610-quad beadchip. 1774
individuals (882 controls, 888 cases) and 541,148 SNPs passed
stringent quality control. Stage 2: We followed up on the strongest
signals from stage 1 (171 SNPs) in an independent Danish sample
which consisted of 1369 cases and 1771 controls after quality control.
Results: Association analysis of the follow-up sample found ten
SNPs with nominal P-values < 0.05, nine of them demonstrating a
directionally consistent replication (lowest P-value = 0.006,
rs4757144). In the combined analysis of stage 1 and stage 2
individuals, rs4757144 on chromosome 11 demonstrated the
strongest association with schizophrenia (P = 1.77 x 10 -6 ). Among
the ten SNPs demonstrating nominal significant association in the
follow-up sample were two moderately independent SNPs
(rs10828623 and rs10741058, r 2 = 0.6) located in the gene CACNB2
on chromosome 10. These two SNPs were also among the 15 most
associated SNPs in the combined analysis. A region-wise association
analysis of stage 1 data summarizing permutation P-values of SNPs
in a region of 100kbp into one P-value, found significant association
of a region placed on chromosome 10 upstream the gene ZEB1 (P =
7.04 x 10 -7 ). The SNP rs3123688 located in this region was the
second strongest in the combined analysis (P = 3.1 x 10 -6 ). In a metaanalysis
analysis including stage 1 and stage 2 individuals and
additional 464 schizophrenia cases and 1,272 controls from a German
sample rs4757144 remained the most significantly associated SNP
(P-value = 3.41x10 -6 ).
Conclusions: rs4757144 is located in the circadian rhythmassociated
gene ARNTL. Circadian-rhythm abnormalities in
schizophrenia and bipolar disorder patients have been reported and
smaller candidate gene studies have investigated the association of
ARNTL with bipolar disorder and schizophrenia with inconsistent
results. Our analyses indicate the implication of two loci on
chromosome 10, one close to the gene ZEB1, which has not
previously been reported in relation to psychiatric diseases and one
containing the gene CACNB2. The region containing this gene was
reported as one of the eight regions demonstrating the strongest
signals in a genome-wide association study of bipolar I disorder in
the Han Chinese population.
78
PP22 COPY NUMBER VARIATION ON CHROMOSOMES 1P
IS ASSOCIATED WITH SCHIZOPHRENIA
D. Tsuang*(1,2), C. Yu(1,2), S. Kim(1), S. Millard(2), L. Leong(2),
S. Meichle(1), J. Silverman(3), L. Siever(3, 4), A. Radant(1,2), E.
Wijsman(1)
1. University of Washington 2. VAPSHCS 3. Mount Sinai School of
Medicine 4. Bronx VA Medical Center
*dwt1@uw.edu
Introduction: Multiple recent studies have used whole-genome
genotyping methods to discover novel structural variations in the
DNA of complex genetic disorders. In schizophrenia, the
identification of novel, rare copy number variations (CNVs) has
generated much excitement. The majority of these CNVs range in
size from a kb to several Mb and are thought to be rare, highly
penetrant, and found in only a small number of individuals (e.g.,

PP23 GENETIC ASSOCIATION STUDIES OF SUICIDE
ATTEMPTS IN MOOD DISORDER PATIENTS
R. Perlis*
Massachusetts General Hospital and Harvard Medical School
*rperlis@partners.org
Introduction: Risk for suicide attempt appears to be in part heritable.
Previous investigations of common variation in psychiatric
phenotypes suggest large sample sizes are required to reliability
identify such variations, and meta-analysis may facilitate this process.
Methodology: Fixed and random-effects meta-analysis were used to
examine data from multiple large mood disorder cohorts. Primary
comparisons considered lifetime suicide attempting individuals
contrasted with non-attempting individuals. In addition to examining
single variants, we investigated aggregate risk scores and pathways
for association with suicide attempt.
Results: No single locus reached a threshold for genomewide
significance. However, polygenic and pathway-based analyses
suggest some shared risk across cohorts. These results will be
discussed in the context of follow-up of genomewide association
results.
Conclusions: These results indicate that individual loci of very large
effect do not appear to contribute to suicide liability in these mood
disorder cohorts. However, they suggest the utility of further
investigation using alternatives to single-variant association tests.
79
PP24 EXPRESSION QUANTITATIVE TRAIT
NUCLEOTIDES (EQTNS) IN THE 15Q25 NICOTINIC
ACETYLCHOLINERGIC RECEPTORS (NACHRS) GENE
CLUSTER ARE ASSOCIATED WITH SMOKING
J. Duan*(1), A. Sanders(1), E. Drigalenko(2), W. Moy(1), L.
Chen(3), L. Bierut(3), J. Freda(1), J. Jacobi(1), D. He(1), M.
Collaboration(4), C. Consortium(5), H. Göring(2), P. Gejman(1)
1. Department of Psychiatry and Behavioral Sciences, NorthShore
University HealthSystem and University of Chicago 2. Department of
Genetics,Texas Biomedical Research Institute 3. Department of
Psychiatry, Washington University 4. Molecular Genetics of
Schizophrenia (MGS) Collaboration 5. Cross-Population Meta-
Analysis (CROSSPOP) Consortium
*jduan@uchicago.edu
Introduction: Common variants at the 15q25 nAChRs gene cluster
(CHRNA5-CHRNA3-CHRNB4) have been found associated with
smoking quantity and nicotine dependence. There are two
independent SNP association signals here across different continental
populations (1) rs16969968, a nonsynonymous SNP at CHRNA5
(Asp398Asn) associated with reduced receptor function, and (2) an
intronic SNP at CHRNA3, rs6495308, without evidence for a
biological mechanism yet.
Methodology: We performed an eQTN mapping on 15q25 nAChR
gene cluster with gene expression data from lymphoblastoid cell lines
(LCLs) from European ancestry (EA) MGS subjects, 446
schizophrenia cases and 457 controls.
Results: We identified eight SNPs associated with CHRNA5
expression (p≤0.05; Bonferroni corrected) but none with CHRNA3 or
CHRNB4. These associations are tagged by two SNPs: (1)
rs12899940 (p=3.0 x 10 -6 ), located within an enhancer sequence ~114
kb downstream from CHRNA5, and (2) rs569207 (p=1.8 x10 -4 ), an
intronic SNP which may affect splicing as it is located 34 bp away
from exon 2 of CHRNA5. The effect of rs569207 on CHRNA5
expression is mainly driven by schizophrenia cases (p=6.48 x 10 -
4 ). Furthermore, while rs569207 is in strong LD with rs6495308
(r 2 =0.90), the SNP tagging the cross-population association with
smoking, LD is weaker for rs12899940 (r 2 =0.22). Next, we tested
rs569207 and rs12899940 for association with smoking in 3,189 EA
and 1,362 African American (AA) daily smokers from MGS. Both
eQTNs were nominally associated with cigarettes per day (CPD) in
the EA sample (rs569207 p=0.013 and rs12899940 p=0.027), while
only rs569207 showed association with CPD in the AA sample
(p=0.007).
Conclusions: The putative eQTNs identified here provide a potential
biological explanation for one of the common variation associations
with smoking in the 15q25 nAChRs gene cluster.

PP25 AN INVESTIGATION OF INHERITANCE PATTERNS
IN CNVS VALIDATES KNOWN LOCI AND SUGGESTS
NOVEL CANDIDATE SCHIZOPHRENIA GENES
ECIP
E. Rees*(1), D. Ivanov(1), M. Ikeda(2), D. Ruderfer(3,4,5), J.
Moran(5), K. Chambert(5), L. Georgieva(1), D. Grozeva(1), S.
Purcell(3,4,5), P. Sklar(3,4,5), M. O'Donovan(1), M. Owen(1), G.
Kirov(1)
1. Cardiff University 2. Fujita Health University 3. Massachusetts
General Hospital and Harvard Medical School 4. Massachusetts
General Hospital 5. Broad Institute
*reeseg@cf.ac.uk
Introduction: Copy number variations (CNVs) at several loci have
an important role within the complex aetiology of Schizophrenia
(SZ). These are deletions at 1q21.1, 3q29, 2p16.3 (NRXN1),
15q11.2, 15q13.3, 17p12, 22q11.2 and duplications at 16p11.2 and
16p13.1. Recent research has also revealed an increased risk of
developing SZ with exonic duplications in VIRP2 and C16orf72.
Through investigating the inheritance patterns of CNVs in 662
Bulgarian offspring-parent trios we aim to assess whether there is an
overrepresentation of transmitted to non-transmitted CNVs at known
SZ loci and identify novel CNV associations.
Methodology: Through Mendelian inheritance, parents heterozygous
for a CNV should transmit it fifty per cent of the time to their
offspring. If CNVs are called incorrectly we would expect an overall
preferential non-transmission and a high false positive rate of de
novos. We tested 662 Bulgarian trios for transmission of CNVs. For
replication we used the publicly available MGS dataset (2903 cases
and 2738 controls), 521 Bulgarian controls, and 143 unrelated cases
from Bulgaria, that passed filtering. All samples were genotyped at
the BROAD Institute on Affymetrix 6.0 arrays. All datasets
underwent the same vigorous quality control procedures, which
included CNVs >= 15kb, >=15 probe coverage and subsequent
filtering with a modified Z-score calling algorithm. Using the
Bulgarian trios as our discovery sample, we selected potential genes
of interest if they were hit by CNVs with a transmission to nontransmission
ratio of 2:0 or better. These genes were then further
investigated in a case-control analysis of trios, cases and controls,
using PLINK.
Results: Before filtering of the trios with the Z-score, there was an
apparent preferential non-transmission of rare (

PP27 ANALYSIS OF ASSOCIATION BETWEEN A GENETIC
MARKER LOCATED IN THE ZNF804A GENE (RS1344706)
AND SCHIZOPHRENIA IN A CASE-CONTROL SAMPLE
FROM INDONESIA
ECIP
N. Dai*(1,2), W. Qin(1,2), M. Wildenauer(1,2), A. Kusumawardhani
and the Indonesian Schizophrenia Genetics Consortium (3), D.
Wildenauer(1,2,5), S. Schwab(1,4)
1. School of Psychiatry and Clinical Neurosciences, The University
of Western Australia, 2. Western Australian Institute for Medical
Research, Centre for Medical Research, The University of Western
Australia 3. University of Indonesia 4. Department of Psychiatry,
University of Erlangen-Nuremberg 5. Centre for Clinical Research in
Neuropsychiatry, Graylands Hospital
*20683868@student.uwa.edu.au
Introduction: ZNF804Acodes for a zinc finger protein with so far
not well defined function. Only recently, reports have shown that
ZNF804A is expressed in mouse embryos, and that expression of
ZNF804A might be up-regulated due to interaction with Hoxc8 as a
downstream target (Chung et al, Journal of Biomedicine and
Biotechnology, 2010). In 2008, O'Donovan and Colleagues reported
strong evidence of association of a single nucleotide polymorphism
located in the ZNF804A genomic region, rs1344706, with
schizophrenia based on a genome wide association scan (O'Donovan
et al., (2008) Nature Genet 40:1053-1055). The initial screen
included 479 cases with schizophrenia and 2937 control individual.
Evidence for association was considerably strengthened by two
subsequent replication phases, as well as by a meta-analysis, included
in the first report. Since then, a number of reports became available
confirming the original finding. Most of these reports are based on
Caucasian samples. Our aim was to study rs1344706, which has
been found to be associated with schizophrenia, but also with
depressive disorders, in a large Asian case control sample from
Indonesia for association with schizophrenia.
Methodology: Cases and controls were recruited in the area of
Jakarta and Bogor through collaboration with psychiatrists from the
University of Indonesia. DSM-IV and ICD-10 diagnosis of
schizophrenia was established using structured interviews (DIPS,
translated into Bahasa Indonesia). Controls were screened for major
psychiatric disorders using a shortened interview version. DNA was
isolated from blood samples using standard procedures. Overall, 1117
control subjects and 1097 cases were included in our studies. A
commercially available TaqMan assay (Applied Biosystems) was
used for genotyping the single nucleotide polymorphism rs1344706.
For quality control, samples were re-genotyped for this specific DNA
variant using an RFLP assay.
Results: No deviation from Hardy-Weinberg equilibrium was seen in
cases or controls. Controls revealed a T-allele frequency of 0.488,
while frequency in cases for the T-allele was 0.529. This resulted in a
P-value of 0.006 (chi2 test). Genotype distribution was also
statistically significantly different between cases and controls
(P=0.027). The odds ratio was 1.179 (95% confidence interval 1.047
– 1.327).
Conclusions: We have been able to show association of rs1344706
with schizophrenia in a large sample from Indonesia. The type of the
associated allele (T-allele) was consistent with previous reports. It is
interesting to note that the Indonesian samples revealed similar allele
frequencies for the T-allele as recently reported for a sample from the
Han Chinese population (Zhang et al, Mol Psych.2011,T -allele
frequency in cases: 0.53, T-allele frequency in controls: 0.46,). Our
results support a potential role of ZNF804A in the etiology of
schizophrenia and show that this is apparently not population
specific.
81
PP28 NEXT-GENERATION ASSOCIATION STUDY OF
UNCOMMON, PUTATIVELY FUNCTIONAL VARIANTS
WITH MAJOR PSYCHOSES
A. Takata*(1,2,3), Y. Iwayama(2), K. Yamada(2), E. Hattori(2), T.
Toyota(2), A. Sano(4), M. Nakamura(4), M. Kato(4), S. Kanba(3), T.
Yoshikawa2(2), T. Kato(1)
1. Laboratory for Molecular Dynamics of Mental Disorders, RIKEN
Brain Science Institute 2. Laboratory for Molecular Psychiatry,
RIKEN Brain Science Institute 3. Department of Psychiatry, Kyushu
University, School of Medicine 4. Department of Psychiatry,
Kagoshima University Graduate School of Medical and Dental
Sciences
*atakata@brain.riken.jp
Introduction: Genome-wide association studies have successfully
identified several common SNPs that are associated with psychiatric
disorders with genome-wide significance. However, all of these SNPs
discovered so far have only weak effects (OR 1.1-1.5). Therefore,
increasing attention is now being paid to uncommon (MAF < 5%)
variants, which may have relatively large effects. In this study, we
tested association between uncommon, putatively functional variants
and major psychoses (schizophrenia and bipolar disorder) based on
two strategies, both of which were driven by the next-generation
sequencing technology.
Methodology: 1) Discovery of candidate variant(s) by exome
sequencing of a patient born of a consanguineous marriage followed
by association study using a case-control cohort. We performed
exome sequencing of a schizophrenic patient born of a
consanguineous marriage using SureSelect Human All Exon Kit and
Illumina Genome Analyzer II. The patient also manifested proximal
limb weakness and muscle biopsy revealed multiple deletions of
mitochondrial DNA. His parents did not have any specific psychiatric
and neurological symptoms. Therefore, recessive inheritance of these
phenotypes was suspected. 2) Association study of uncommon,
putatively functional variants discovered in the 1000 Genomes
Project. We selected candidate variants from the 1000 Genomes
Project data released in December 2010 with these criter ia, 1)
Specific in Asian, 2) in the databases of schizophrenia or bipolar
genes (SZGene or Bipolar Disorder Gene Database), 3) nonsynonymous
and splice site variants predicted to be damaging, 4)
Phred score >10, 5) MAF < 5%.
Results: Results of 1). By exome sequencing, total 20317 of coding
variants were identified. Among them, 65 variants satisfied these
criteria, 1) not in dbSNP130, 2) not in HapMap exomes, 3) not in inhouse
data of healthy Japanese, 4) non-synonymous or splice site
variants, 5) homozygous (variant frequency > 75%). When we sorted
these remaining variants by conservation score (PhyloP score), a
missence variant in CNTNAP2 (V786L), whose copy number
variations were known to be associated with autistic spectrum
disorders and schizophrenia, ranked at the top. This variant was not
private and detected in other Japanese with low frequency. Then, we
tested association of this variant with schizophrenia using a Japanese
case-control cohort (2011 cases and 2169 controls). However, four of
controls, as well as five of cases, carried this variant in a homozygous
state and we could not observe significant difference. Results of 2).
Total 47 variants in genes including ADRA1A, ANK3, ERBB3,
GRIN3A and HTR1E remained.
Conclusions: Conclusions of 1). This result indicates that even
putatively functional variants in strong candidate genes are not
necessarily associated with disease. Conclusions of 2). These
variants are good candidates for further investigations. Associations
of these variants with major psychoses were, and will be studied
using previously described schizophrenia case-control cohort and
bipolar case-control samples.

PP29 ALTERATIONS IN WNT/β-CATENIN PATHWAY
MRNA EXPRESSION LEVELS IN MODIFIED
ELECTROCONVULSIVE THERAPY
M. Nishiguchi*, A. Tsutsumi, T. Kanazawa, H. Kikuyama, J. Koh,
H. Yoneda
Osaka Medical College
*psy062@poh.osaka-med.ac.jp
Introduction: Modified electroconvulsive therapy (m-ECT) is one of
the treatment options with high efficacy and safety, for drug
treatment-resistant depression or schizophrenia, although the
mechanism of m-ECT in the human brain is not fully understood. As
for the mechanism of antidepressant treatment, the series of research
on the postmortem brain pointed out the involvement of BDNF
(brain-derived neurotrophic factor) gene through the hippocampal
neurogenesis. Moreover, increased BDNF gene expression was also
found in the treatment of m-ECT. Therefore the explanation of both
treatments is possible only on BDNF gene, however the gene
influences too many organs and illnesses.
Wnt signaling pathway has received a lot of attention of
neurogenesis. GSK3β can be suppressed by binding Wnt to frizzled
receptor, and β-catenin migrate to the nucleus with accumulating in
cells as free form without being GSK3β phosphorylated. β-catenin
begins the transcription of Wnt target genes by composing complex
with T cell factor, which biological reaction is essential for cell-cycle
rotation.The proliferation of neural stem cells rises by the
accumulation of β-catenin in the nucleus. Especially the Yamanaka
four transcription factor (sox2, oct-4, klf-4, c-myc) in Wnt signaling
pathway is indispensable for the first-generation iPS(induced
pluripotent stem cell). We aimed to the reveal association between
the pre- and post- m-ECT with analyzing these four transcription
factors mRNA expression changing.
Methodology: 15 patients with treatment resistant depression were
enrolled for the current study. Gene expression was carried out by
RT-PCR method.
Results: We will report the effect of m-ECT and four genes in Wnt
signaling pathway.
Conclusions: Further evaluations of this relationship in larger
samples should help clarify the nature relationship between m-ECT
and neurogenesis.
82
PP30 INVESTIGATION OF DNA POLYMORPHISMS IN A
LARGE SAMPLE OF HEROIN ADDICTED INDIVIDUALS
FROM WESTERN AUSTRALIA TREATED WITH
NALTREXONE IMPLANTS FOR ASSOCIATION WITH
ADDICTION SUSCEPTIBILITY AND TREATMENT
RESPONSE
S. Schwab*(1,2), N. Morris(2), A. Scott(2), D. Wildenauer(2,3), G.
Hulse(2)
1. University of Erlangen-Nuremberg 2. University of Western
Australia 3. Centre for Clinical Research in Neuropsychiatry
*sibylle.schwab@uk-erlangen.de
Introduction: The population prevalence of heroin addiction in the
adult Australian population aged between 15 and 54 is estimated to
be in the range of 7 per 1000. It has been shown that susceptibility to
heroin dependence is strongly influenced by genetic factors with
heritability estimates as high as 0.7 and most likely a small number of
genes as well as environmental factors contributing. Pharmacological
treatment options are based on interaction with the u-opioid receptor.
One of the most common treatments includes the substitution of the
stimulating agent heroin with methadone. Another treatment option is
based on blocking the u-opioid receptor with naltrexone, making it
unavailable for heroin. For our study we had access to a heroin
addicted population from Western Australia who underwent
treatment with naltrexone implants.
Methodology: We have ascertained 896 individuals with DSMIV
confirmed diagnosis of heroin dependence in Western Australia. All
of the individuals have been treated using naltrexone implants.
Plasma levels of naltrexone and its primary metabolite, naltrexol, are
available. In addition, data on first use of heroin, switch to regular
use of heroin, and co-morbidity with other drug abuse have been
collected. DNA of these samples had been isolated for genotyping
candidate genes and for GWAS.
Results: Overall, 768 markers from 108 candidate genes were
successfully genotyped using a GoldenGate assay (Illumina). These
polymorphisms are currently being analysed for association with
susceptibility to addiction as well as for a possible impact on
response to naltrexon implants.
Conclusions: A large sample of heroin addicted individuals with
naltrexone treatment is available for genetic studies into addiction
and treatment outcome.

PP31 GENOME-WIDE ASSOCIATION META-ANALYSIS OF
TOTAL BRAIN VOLUME: RESULTS FROM THE ENIGMA
CONSORTIUM
A. Arias-Vásquez*
On behalf of the ENIGMA consortium:
http://enigma.loni.ucla.edu/publications/ohbm2011/
*a.ariasvasquez@psy.umcn.nl
Introduction: There is evidence for shared genetic factors explaining
part of the variance of brain structure, regional brain volumes and
psychiatric phenotypes. The rationale behind this approach is that
differences of brain volume, either global or regional, are related to
their specific functioning and to more global cognitive processes. Our
overall aim is to identify common genetic variants that modify the
risk for psychiatric disorders (in particular attention
deficit/hyperactivity disorder (ADHD)) based on the identification of
genetic variants involved in the variance of the volume of brain
structures in healthy individuals.
Methodology: The mean total brain volume was automatically
segmented in T1-weighted MRI scans from all contributing groups
using the software package FreeSurfer. 16 groups worldwide have
now pooled their imaging genomics data from a total of >7000
subjects, boosting the power to detect effects that no single study
could identify. Genetic homogeneity of the samples was assessed via
multi-dimensional scaling plots. Genotypes were imputed using the
HapMap III reference panel, and associations were tested via dosage
of each imputed SNP (accounting for kinship in family-based
samples). Imputed SNPs were quality controlled, via an automated
system, to filter out SNPs with low frequency or poorimputation
quality. Results files and summary statistics from each group were
pooled for meta-analysis which was conducted at each SNP across all
groups.
Results: By February 2011, 17 groups had uploaded GWAS results
in >7000 subjects. Association conducted at ~1.3 million autosomal
SNPs showed that none of the individual sites contained genomewide
significant GWAS results (p

PP33 A GENOME-WIDE CNV ASSOCIATION STUDY
ON AUTISM SPECTRUM DISORDER (ASD) IN THE
JAPANESE POPULATION
X. Liu*(1), K. Tokunaga(1), T. Sasaki(2)
1. Department of Human Genetics, Graduate School of Medicine,
The University of Tokyo 2. Laboratory of Health Education Graduate
School of Education and Office for Mental Health The University of
Tokyo
*liuxiaoxi@m.u-tokyo.ac.jp
Introduction: Family and twin studies have strong evidence that
autism spectrum disorder has a strong genetic background
however,all know variation only accounts for a small fraction for
known patitens. We conducted a genome-wide copy number
variation (CNV) association study on ASD in the Japanese
population.
Methodology: Participants consisted of 500 ASD trio Japanese
CNVs were detected using Genome-Wide Human SNP array
6.0 and determined by Penncnv. CNVs with length

PP35 GENOME-WIDE ASSOCIATION STUDY IDENTIFIES
GENETIC LOCI ASSOCIATED WITH BODY MASS INDEX
AND HDL-CHOLESTEROL LEVELS DURING
PSYCHOPHARMACOLOGICAL TREATMENT
L. Athanasiu*(1,2,3), A. Brown(1,4), A. Birkenaes(1), M.
Mattingsdal(3,5), I. Agartz(1,6), I. Melle(1,3), V. Steen(7,8), O.
Andreassen(1,3), S. Djurovic(1,2,3)
1. Institute of Clinical Medicine, University of Oslo 2. Department of
Medical Genetics, Oslo University Hospital 3. Division of Mental
Healt and Addiction, Oslo University Hospital 4. Department of
Biostatistics, University of Oslo 5. Research Unit, Sorlandet Hospital
6. Department of Psychiatric Research, Diakonhjemmet Hospital 7.
Dr.Einar Martens Research Group for Biological Psychiatry,
Department of Clinical Medicine, University of Bergen 8. Center for
Medical Genetics and Molecular Medicine, Haukeland University
Hospital
*lavinia.athanasiu@medisin.uio.no
Introduction: Metabolic and cardiovascular side effects are of major clinical
importance because of their relevance for the increased mortality seen in
severe mental disorders, which is mainly due to increased somatic morbidity.
A better understanding of the mechanisms underlying metabolic and
cardiovascular adverse effects associated with current psychopharmacological
drugs is therefore imperative, and can lead to development of more tolerable
drugs and personalized treatment based on the patient's genetic variants, as
well. We performed a genome-wide association study of metabolic and
cardiovascular risk factors during pharmacological therapy in patients with
severe mental disorders
Methodology: Our sample consisted of 594 patients with a severe mental
disorder (schizophrenia or bipolar disorder) from the Thematically Organized
Psychosis (TOP) Study and were successfully genotype on Affymetric
Genome-Wide Human SNP array 6.0 (Affymetrix Inc., Santa Clara, CA,
USA) The patients were examined for twelve indicators of metabolic side
effects (body mass index, waist circumference, total cholesterol, HDLcholesterol,
LDL-cholesterol, HDL-cholesterol/total cholesterol ratio,
triglycerides, glucose, and C-reactive protein), and cardiovascular variables
(blood pressure and heart rate) were measured. The patients used
antipsychotics, mood stabilizers and/or antidepressants. We analyzed
interactions between gene variants and three categories of
psychopharmacological agents based on their reported potential for side
effects and defined genome-wide significance based on false discovery rate
(FDR) of 0.1. We investigated these interactions between SNP and the
medication with respect to differences in the level of metabolic- and
cardiovascular side effects, using linear regression models implemented in
PLINK.
Results: The analyses revealed 14 significant interactions (FDR

PP37 SCHIZOPHRENIA TWO-HIT HYPOTHESIS IN VELO-
CARDIO FACIAL SYNDROME
H. Williams*, M. O'Donovan, M. Owen
MRC centre for neuropsychiatric genetics and genomics, Department
of psychological medicine, Cardiff University, CF14 4XN
*williamshj1@cf.ac.uk
Introduction: Velo-cardio facial syndrome (VCFS) is a common
microdeletion syndrome associated with a number of wide ranging
phenotypes. Of major interest is the observation that VCFS patients
exhibit an elevated rate of schizophrenia that is some 30 times that of
the general population. Although much work has been conducted
within the 22q11.2 deletion region to elucidate the source of this
elevated risk there are no genetic markers that can distinguish
between VCFS subjects that develop schizophrenia and those that do
not. This observation has led to the suggestion that a schizophrenia
risk locus may reside outside the deleted region and may modulate
the risk via a two-hit model.
Methodology: We sought to test whether secondary copy number
variants (CNVs) could be responsible for the development of
schizophrenia in a proportion of the sample of VCFS patients (n=48)
where half (n=24) had a diagnosis of psychosis. We used genomewide
microarrays to identify large (>100kb), rare (

PP39 META-ANALYSIS OF SIX GENOME-WIDE
ASSOCIATION STUDIES OF ADHD IN ADULTS
D. Boomsma*(1), V. Saviouk(1), A. Arias-Vásquez(2), N. Amin(3),
J. Hottenga(1), B. Penninx(4), J. Smit(4), E. de geus(1), S. Kooij(5),
C. van Duijn(3), B. Franke(2)
1. Biol Psychol, VU Univ 2. Human Genetics, Radboud University
Nijmegen Medical Center 3. Dept Epidemiology, Erasmus Univ
Medical Center 4. Dept Psychiatry, VU Univ Medical Center 5.
PsyQ, Dept adult ADHD
*di.boomsma@psy.vu.nl
Introduction: Although apparently lower than in children, the
heritability of ADHD in adults is significant. In the Netherlands we
have collected genome-wide SNPs and phenotype data on adult
ADHD in four population based samples, one sample of parents of
children ascertained for childhood ADHD and in one cohort which
was ascertained for major depressive disorder (MDD).
Methodology: The samples derive from 3 projects in Nijmegen
(IMAGE, BIG and NBS, total N = 2190), from the Netherlands Twin
Register (NTR, N = 2143) and from the Erasmus Rucphen Family
study (ERF, N = 1054). The clinical cohort comes from the
Netherlands Study of Depression and Anxiety (NESDA, N = 1001).
In all studies ADHD was assessed by self-report: the Conners Adult
ADHD Rating Scales (CAARS) were used in NTR and ERF and the
23 item ADHD Rating Scale questionnaire was employed in the
Nijmegen samples. Phenotypic scores were obtained for Inattention
and Hyperactivity domains, as well as for ADHD symptoms. After
thorough genotyping quality control and imputation using MACH
and HAPMAP European Reference Set, ~2.3 mln SNPs were
analyzed for each study/phenotype using MACH2QTL with an
additive model and sex/age as covariates. Currently, a meta-analysis
of the genome-wide association scans is being performed using all
samples.
Results: First results from the NTR group demonstrate a genomewide
significance for the cumulative ADHD Index in CAARS at
rs6119272 (20q11, p=2.4E-10) within a putative protein. Another two
significant hits were within ALDH1A2 (rs4646591, p=3.57E-9) and
RORA (rs12324535, p=3.44E-8) genes. Other top genes in
preliminary results included: ADHD Index - CYP2A6, SCGN,
CSMD1, ATM, UBE2R2, UBAP2, RBMS3, WWOX, GALNT14;
Inattention - ALDH18A1, PROX1, UHRF1BP1, SNRPC, GATM,
HPS5, NAV3, APOB, CMPK1, MUC5AC; Hyperactivity -
ADAMTS17, HYAL3, ACPL2, RASSF1, GPC5, GCN1L1,
SLC6A2, NLRP12, ZNF234, PRKD1. Cadherin 13, or CDH13, one
of the top candidates for ADHD, gave a p-value 9.79E-5 at
rs6563978 and was among top 100 genes for Inattention in a cohort
with MDD. Interestingly, other cadherins were also seen among top
genes for the ADHD index (PCDH7, p=0.0001 and CDH2,
p=0.0002) in the MDD cohort. Meta-analysis of NTR and NESDA
samples also point to PCDH15 and CDH28 as possible influencing
factors for ADHD index and PCDH9 and CDH12 for
inattention. Among other overrepresented gene families in the results
were Usher syndrome genes and CUB and Sushi multiple domains
genes (CSMD) that recently were shown to be involved in addiction
phenotypes, known to be associated with ADHD.
Conclusions: Results of GWAS of ADHD symptoms assessed by
self-report in the population overlap with findings from clinical
samples. If confirmed in the final meta-analysis in the current study,
this would open up new routes towards the identification of new
ADHD genes.
87
PP40 GENOME-WIDE SNP-SNP INTERACTION ANALYSIS
IN BIPOLAR DISORDER
T. Mühleisen*(1), M. Mattheisen(2), F. Degenhardt(1), T.
Becker(3), M. Steffens(3), S. Herms(1), B. Haenisch(1), J.
Strohmaier(4), B. Bohn(14), T. Gerstner(14), M. Griebel(14), W.
Maier(15), P. Propping(1), M. Rietschel(4), M. Nöthen(1), S.
Cichon(1,16)
1. Inst Hum Genet, Dept Genomics, Life & Brain Ctr, Univ Bonn 2.
Dept Biostatistics, Harvard School of Public Health 3. IMBIE, Univ
Bonn 4. Dept Genet Epidemiol in Psychiatry, Central Inst Mental
Health 5. IMIBE, Univ Duisburg-Essen 6. Inst Epidemiol, Helmholtz
Zentrum München, German Res Ctr for Environmental Health 7. Inst
Clinical Mol Biol, Univ Kiel 8. MPI Psychiatry 9. Psychiatric Ctr
Nordbaden 10. Dept Psychiatry, Univ Würzburg 11. Dept Psychiatry
and Psychotherapy, Univ Hospital 12. Dept Clinical and
Developmental Psychology, Inst Psychology, Univ Tübingen 13.
Dept Psychiatry and Psychotherapy, Univ Göttingen 14. Inst for
Numerical Simulation, Univ Bonn 15. Dept Psychiatry, Univ Bonn
16. INM-1, Res Ctr Juelich
*thomas.muehleisen@uni-bonn.de
Introduction: In recent years, genome-wide association studies
(GWAS) have identified many common single-nucleotide
polymorphisms (SNPs) that contribute to complex traits. However,
there is still missing heritability in genetically-complex traits,
including bipolar disorder (BD) and other common neuropsychiatric
diseases. Although this might be explained by overestimation of
heritability, it could be explained in part by yet unidentified common
variants with very small genetic effect sizes, or by epistatic effects
(interaction) between genetic variants. Due to the high number of
possible SNP-SNP interaction pairs arising from typical microarraybased
GWAS datasets (about 500K SNPs), genome-wide interaction
analysis (GWIA) are computationally challenging (about 1.0E11 SNP
pairs).
Methodology: In the present study, we applied a novel approach for
GWIA to a dataset of 473,227 SNPs from 1,158 patients with a
DSM-IV diagnosis of BD and 2,172 population-based controls, all of
German ancestry. This approach has been implemented in the latest
version of the program INTERSNP (Herold et al. 2009).
Results: Given the genome-wide significance at the 0.05 level for
genotypic interaction and a marker set with 500K SNPs (P=1.0E-12
Becker et al. 2010), we found a genome-wide significant interaction
between a SNP in the gene B3GALTL on chromosome 13q12 and a
intergenic SNP on chromosome 11q24 (P=9.49E-13). The B3GALTL
marker also participates in the second most significant pair by
interacting with another SNP on chromosome 11q24, which is in
strong linkage disequilibrium with the 11q24 SNP of the top finding
(r-squared greater than 0.8).
Conclusions: This supportive result suggest that there is a truepositive
interaction between the loci 13q12 and 11q24 in bipolar
disorder. Our main GWIA finding, however, requires evidence for
replication. For this purpose, we are currently following-up our top
results in large independent samples of bipolar disorder. The results
will be presented at the conference.

PP41 FUNCTIONAL REGULATION OF THE AHI1 GENE IN
SCHIZOPHRENIA VIA A DISTANT METHYLATION OF AN
ALTERNATIVE (TSS) PROMOTER: A HYPOTHESIS
IMPLICATING THE ROLE OF LINE ELEMENTS
F. Macciardi*(1,3), T. Zemojtel(2), F. Torri(1,3), E. Osimo(3), B.
Lerer(4), S. Gaudi(5)
1. Dept of Psychiatry and Human Behavior, UCI 2. Max Plank
Institute for Molecular Genetics 3. Universita' degli Studi di Milano
4. Hadassah Medical Organization 5. Department of Infectious,
Parasitic and Immune-Mediated Diseases, Italian National Institute of
Health
*fmacciar@uci.edu
Introduction: The Abelson Helper Insertion virus 1 (AHI1) is a
schizophrenia-associated gene that we originally discovered (Lerer et
al, 2003) and later confirmed (Amann et al, 2005). Since then, many
other investigators also confirmed the association of AHI1 to
schizophrenia in other populations (Ingason et al, 2005 and 2010).
More recently, we fine-mapped the entire 1M bp genomic region of
AHI1, extending our analyses to the population-specific evolution of
the gene and its regulatory network (Torri et al, FASEBJ, 2010).
This initial annotation was a first step to characterize the functional
role and regulation of AHI1 in schizophrenia. Intriguingly, one of the
highest associated SNP, which has been also extensively replicated
by others in several papers as well as in a recent meta-analysis, is
rs1475069 (A/C) that lies at a great molecular distance (~ 250,000
bp) from the 5' end of the gene.
Methodology: We have re-sequenced the 1M bp region around the
AHI1 gene in extremely different subjects (those who do and those
who do not present the risk alleles at SNPs associated to the disease)
in our initial discovery population. We also sequenced wholegenomes
from additional 25 schizophrenic patients from other
populations, looking for SNPs and other genomic signatures in and
around AHI1. In other subjects, we have performed a MeDIP-Seq in
post-mortem brain tissues.
Results: Preliminary annotation from one of us (T. Z.) has shown
that the SNP is located in a pretty well conserved region of ~40nt.
The "C" variant creates a "CpG" dinucleotide and the latter might be
subject to methylation. Another "CpG" dinucleotide -- which is
directly upstream of the SNP-- is methylated. The methylation data
was generated by application of MeDIP-seq in the context of brain
tissue (postmortem human frontal cortex gray matter). Also, a TAF1
binding signal is present immediately downstream the SNP (see also
a small cluster of DNaseI hypersensitivity signal). The latter might
indicate that the region containing the SNP could be serving as a
functional promoter/enhancer (TSS). In fact, a CAGE tag (identified
in HepG2) maps in this region, starting just one nucleotide (nt)
upstream the SNP. The tag contains a mutation at the 2nd nt, which
corresponds to the location of the SNP
Conclusions: The above evidence suggests a functional-promoterregion
scenario. Given the unusually wide-spreading distribution and
large number of close to very distant eQTLs regulating the expression
of AHI1, SNP rs1475069 could be another eQTL for the gene.
Alternatively, this hypothetical promoter may be functionally related
to the L1PA3 Transposable Element lying nearby, regulating AHI1
via specific transcripts.
88
PP42 GENOME-WIDE ASSOCIATION STUDY OF
ANXIETY-SPECTRUM DISORDERS IN TWO CAUCASIAN
COHORTS
T. Otowa*(1), S. Aggen(1), E. Castelao(2), Z. Kutalik(2), B.
Maher(3), E. van den Oord(1), M. Preisig(2), J. Hettema(1)
1. Virginia Commonwealth University 2. University of Lausanne 3.
Johns Hopkins University
*totowa@vcu.edu
Introduction: Studies of anxiety disorders (ADs) in families and
twins have demonstrated that genetic factors account for about 50%
of their pathophysiology, while the susceptibility genes of ADs have
not been elucidated. Considering high comorbidity of ADs with each
other, there may be common genetic risk factors among ADs. To
identify genetic variants contributing to AD susceptibility, we
performed genome-wide association studies (GWAS) in two
independent cohorts with anxiety-related phenotypes.
Methodology: The first sample consisted of 2725 subjects from the
Molecular Genetics of Schizophrenia (MGS) study control sample.
The second sample comprised 2027 subjects from a population-based
cohort (PsyCoLaus). These Caucasian samples were genotyped on
the Affymetrix 6.0 platform and 500K GeneChip, respectively. We
applied factor analysis to generate factor scores for a common AD
phenotype as a quantitative trait in association analysis. Logistic
regression for the factor score was carried out in each sample,
correcting for population ancestry. These results were compared to
those from more traditional case-control analyses.
Results: After the data cleaning and quality control of genotype data,
626,833 SNPs (MGS) and 331,798 SNPs (PsyCoLaus) on autosomal
chromosomes were further analyzed. Neither GWAS identified any
SNP posessing genome-wide significance. A preliminary metaanalysis
of the two GWAS also did not produce any genome-wide
significance results. The strongest association in the meta-analysis
was observed at the SNP rs2947344 near ARHGAP22 on 10q11 (P min
= 5.8 x 10 -6 ). Several moderate associations of SNPs in prior
candidate genes were also identified (eg. CNTNAP2 and PDE4B).
Conclusions: The present study identifies several SNPs associated
with ADs which are worthy of further investigation. However, our
results suggest that SNPs with major effects on ADs are unlikely to
exist. Meta-analysis of larger sample sizes will be needed to identify
novel candidate genes for ADs.

PP43 HIGH RESOLUTION ASSESSMENT OF COPY
NUMBER VARIATION IN EIGHT PAIRS OF
MONOZYGOTIC TWINS DISCORDANT FOR
SCHIZOPHRENIA OR BIPOLAR DISORDER
R. Bloom*(1), A. Kähler(1,2,3), A. Collins(1), G. Chen(4), T.
Cannon(5), C. Hultman(2), P. Sullivan(1)
1. Department of Genetics, University of North Carolina at Chapel
Hill 2. Department of Medical Epidemiology and Biostatistics,
Karolinska Institutet 3. Department of Psychiatry, Oslo Univeristy
Hospital - Ulleval 4. Department of Biostatistics, University of North
Carolina at Chapel Hill 5. Departments of Psychology, Psychiatry,
and Human Genetics, University of California at Los Angeles School
of Medicine
*rbloom@email.unc.edu
Introduction: Schizophrenia and bipolar disorder have a
concordance rate of about 50% in monozygotic twins, suggesting a
complicated combination of genetic, epigenetic and environmental
factors contributing to the etiology of these psychiatric diseases.
Copy number variation (CNVs) is an important source of genetic
variation, and CNVs play a clear role in the etiology of many
psychiatric diseases, including schizophrenia and bipolar disorder.
Methodology: Using the Swedish Twin Registry, we ascertained and
clinically evaluated eight pairs of monozygotic twins where one twin
has schizophrenia or bipolar disorder and the other is unaffected.
Monozygosity was confirmed using genotyping. Using DNA from
peripheral blood, we are using array-based comparative genomic
hybridization (aCGH) to detect CNVs that arose in mitosis. Using
two-channel arrays, we compare the affected to the unaffected twin in
order to enhance specificity. Moreover, we have used two different
aCGH platforms (Nimblegen's 2.1M probe array and Agilent's
SurePrint G3 1x1M array) in order to conduct an unbiased genome
screen and to enhance accuracy. Segments of copy number variation
were called with genoCN, and we are currently verifying copy
number changes by additional methods.
Results: Preliminary results identified no large CNVs but varying
CNV burden across the different twin pairs. We observed CNV
differences between twins in regions known to undergo mitotic
rearrangements (e.g., areas of T cell receptor recombination).
Conclusions: Genetic mosaicism may make it harder to detect CNVs
and we are therefore developing techniques to work around these
issues. Further analysis will provide an in-depth look at genetic
differences between monozygotic twins, as well as provide insight
into different aCGH technologies.
89
PP44 ADDITIONAL SUPPORT FOR CACNA1C AND
CHROMOSOME 15Q14 AS SUSCEPTIBILITY LOCI FOR
BIPOLAR DISORDER
E. Green*(1), M. Hamshere(2), D. Grozeva(1), I. Jones(1), L.
Jones(3), K. Gordon-Smith(1,3), L. Forty(1), J. Moran(4), J.
Kranz(4), S. Purcell(4), P. Sklar(4), M. Owen(1), M. O'Donovan(1),
N. Craddock(1)
1. MRC Centre for Neuropsychiatric Genetics and Genomics, Dept.
of Psychological Medicine, Cardiff University 2. Biostatistics and
Bioinformatics Unit, MRC Centre for Neuropsychiatric Genetics and
Genomics, Cardiff University 3. Department of Psychiatry,
University of Birmingham 4. Stanley Centre for Psychiatric
Research, Broad Institute
*greenek@cf.ac.uk
Introduction: A recent meta-analysis of genome-wide association
studies on bipolar disorder (BD) (4,387 cases and 6,209 controls) by
Ferreira et al. 2008 identified a strong association with ANK3
(ankyrin G), provided independent support for the association with
CACNA1C (alpha 1C subunit of the L-type voltage-gated calcium
channel) and identified a third region of association on chromosome
15q14.
Methodology: We have genotyped new samples consisting of 1238
BD and 2913 controls on the Illumina platform using the
immunochip. The most associated directly genotyped and imputed
SNPs for the 3 regions (ANK3, CACAN1C and chromosome 15q14)
from the meta-analysis with a p value less than 10 -6 were
genotyped. Fine mapping was also performed genotyping SNPs
within a recombination region around the most highly significant
SNPs in ANK3 and CACAN1C (rs10994336 and rs1006737
respectively).
Results: An association was seen with rs1006737 in CACNA1C with
the same risk allele. Fine mapping of the recombination region
around rs1006737 did not refine the signal, rs1006737 remained the
most associated SNP (Trend P = 5.8x10 -4 ). We also noted support for
the previously identified SNPs on chromosome 15q14 (rs12899449 &
rs2172835, Trend P = 0.055 and 0.035 respectively). We saw no
replication for the 2 SNPs that previously showed strongest
association in ANK3, nor in the SNPs genotyped in the
recombination region around rs10994336.
Conclusions: In summary, our study supports the findings that
CACAN1C and the chromosomal region on chromosome 15q14 as
bipolar disorder susceptibility loci.

PP45 DE NOVO CNVS AFFECTING MULTIPLE
GENES/PATHWAYS MAY EXPLAIN DISCORDANCE OF
MONOZYGOTIC TWINS FOR SCHIZOPHRENIA
C. Castellani*, R. O'Reilly, S. Maiti, S. Singh
The University of Western Ontario
*ccastel3@uwo.ca
Introduction: Schizophrenia is a common (1%) psychiatric disorder
of high heritability (80%) and low concordance (48%) between
monozygotic twins. Such epidemiological features are best explained
by involvement of multifactorial genetic, epigenetic and
environmental interactions. Given the multifactorial heterogeneity
implicated in this disease we feel that an explanation for the
discordance of MZ twins (MZD) using genome-wide comprehensive
analysis of twins may offer genetic insight into the causation of this
disease. Specifically, we report on genome-wide copy number
changes (CNCs) between six MZD twin pairs that allow
identification of pair specific de novo CNCs that may explain their
discordance.
Methodology: We (O’Reilly, Psychiatrist) identified six pairs of
monozygotic twins discordant for schizophrenia and collected their
blood and cheek swab samples following informed consent and ethics
approval for this research by the Committee on Research Involving
Human Subjects of the University of Western Ontario. This DNA
was hybridized on Affymetrix Human SNP Array 6.0 that includes
1.8 million markers. CNVs were called by Affymetrix Genotyping
Console 4.0 as well as Partek Genotyping Suite software suites.
Results: Twin pairs differed for a minimum of one to thirteen CNVs.
The best explanation for the observed differences in CNVs between
MZ twins is de novo mutation (DNM) occurring during early
embryogenesis. This explanation was confirmed in two of the six
pairs using parental genotypes. Conceptually, DNMs may also lead to
varying degrees of mosaicism, an unrecognized form of genomic
variability affecting genetic individuality. Our analysis shows that
each pair of MZD differs for a number of genetic features including
SNP and CNVs. More important, the SNP and CNV differences
between ill and well twin invariably affect a set of genes that are
implicated in neurodevelopment and already reported as potential
contributors to schizophrenia by family and population studies. The
results argue for extensive heterogeneity and offer independent
support for the involvement of these genes in the development of
schizophrenia. We found that each of the six MZD pairs is different
with respect to the schizophrenia related gene(s) affected. The only
common pathway affected in more than one pair involves olfactory
receptors that have been implicated in the development of
schizophrenia. It is likely that the genetic differences across twins
represent the heterogeneous manifestation of the disease including
age of onset.
Conclusions: The results show genome wide de novo changes are
common during ontogeny. Depending on the nature of changes and
the genes involved they may contribute to discordance of MZD twins
for any feature including disease. The fact that different MZD pairs
have identified different genes offers support for the extensive
genetic heterogeneity in schizophrenia and may argue for the need for
“patient specific” etiology and treatment strategies for schizophrenia.
90
PP46 FAMILY-BASED WHOLE GENOME SEQUENCING
OF SCHIZOPHRENIA
S. McCarthy*(1), J. Badner(2), W. McCombie(1), W. Byerley(3)
1. Cold Spring Harbor Laboratory 2. University of Chicago Medical
Center 3. University of California San Francisco
*mccarthy@cshl.edu
Introduction: Schizophrenia is a severe neuropsychiatric disorder
that affects approximately 1% of most populations. Despite evidence
for a large heritable component in schizophrenia, the identification of
genetic risk factors has been very difficult due the genetic and
phenotypic complexity of the disorder. Genome-wide association
data suggest that common variants with small effect sizes may
explain 2-30% of the genetic liability to schizophrenia. Although the
global contribution of rare variants to schizophrenia susceptibility is
unclear, the association of rare recurrent CNVs and an elevated CNV
burden suggests that a spectrum of disease variants below the
resolution of array-CGH may be family and individual specific.
Methodology: We are combining the power of whole genome
sequencing with the advantages of family based designs to identify
rare genetic variants of large effect that significantly predispose
carriers to schizophrenia in large multiplex families. We are in the
process of sequencing the whole genome of 10 individuals from two
families of European ancestry on Illumina's HiSeq2000. At least
three affected members and one unaffected representing several
family branches are being sequenced.
Results: We recently completed sequencing all members from one
family and data analysis is underway. Although we expect to
discover a large number of variants genomewide, we aim to narrow
the search for risk variants by first focusing our attention on shared
rare variants and CNVs disrupting coding exons, UTRs and
promoters in regions of linkage previously detected in these
pedigrees. Variants discovered using our approach will be followed
up in additional available family members
Conclusions: Whole genome sequencing represents a unique and
long desired opportunity to gain signficant insights into the genetics
and biology of all psychiatric conditions. Coupling whole genome
sequencing with family based study designs will be an important
strategy to rapidly identify risk variants and genes that elevate the
liability to schizophrenia thereby promoting improved diagnosis and
potentially better theraputics at the personal and family level.

PP47 IDENTIFYING MOOD DISORDER SUSCEPTIBILITY
LOCI IN A DENSELY AFFECTED PEDIGREE FROM THE
ANDALUCIAN REGION OF SPAIN
A. Collins*(1), R. Bloom(1), Y. Kim(1), M. Nöthen(2), S. Cichon(2),
M. Rietschel(3), P. Sullivan(1)
1. Department of Genetics, University of North Carolina at Chapel
Hill 2. Institute of Human Genetics, Department of Genomics,
University of Bonn 3. Department of Genetic Epidemiology in
Psychiatry, Central Institute of Mental Health Mannheim, University
of Heidelberg
*collina@med.unc.edu
Introduction: Mood disorders have a lifetime prevalence of
approximately 20% in adults in the United States, with a 3.9%
prevalence for bipolar disorder. Both major depressive disorder and
bipolar disorder are thought to have a strong genetic component
however, both disorders display complex genetics and high degrees
of heterogeneity. The use of large pedigrees with high prevalence
may reduce heterogeneity and select for variants of large effect,
allowing easier mapping of disease loci. We have therefore identified
a large multigenerational pedigree densely affected with bipolar
disorder. The pedigree has five generations descended from a single
founder pair. There was limited in-migration into the region where
the pedigree members lived. The pedigree contains 18 individuals
with bipolar disorder (including a sibship with six of eleven
individuals affected) and seven individuals with recurrent major
depression.
Methodology: We have applied multiple complementary genomic
technologies to this pedigree, including SNP genotyping using the
Illumina Omni 1M chip, copy number variation mapping using
Nimblegen aCGH tiling arrays, and exome sequencing of affected
individuals.
Results: Shared segment analysis using SNP genotypes from eleven
individuals affected with bipolar disorder have yielded regions of the
genome as potential candidates, including a 4Mb region on chr18
shared by seven bipolar I cases. Copy number analysis did not reveal
any large, novel, and potentially causative CNVs. Exome sequencing
results will be prioritized by potential candidate regions.
Conclusions: This family appears to carry a genetic factor increasing
risk for mood disorders, including bipolar disorder. While we have
identified regions of potential interest, our current analyses have not
explained the incidence of mood disorders seen in this densely
affected pedigree. Careful evaluation of these regions within
additional family members and additional genetic follow-up will be
necessary to identify the causative loci in this pedigree.
91
PP48 INTEGRATING BIAS CORRECTION IN READ-DEPTH
ANALYSIS OF WHOLE GENOME SEQUENCING DATA TO
IDENTIFY COPY NUMBER GAIN AND LOSS
ECIP
J. Szatkiewicz*(1,2), W. Wang(4), W. Sun(1,3), W. Wang(4), D.
Lin(3), P. Sullivan(1,2)
1. Department of Genetics 2. Department of Psychiatry 3.
Department of Biostatistics 4. Department of Computer Science
*jin_szatkiewicz@med.unc.edu
Introduction: Copy number variation (CNV) has been shown to play
an important role in the etiology of schizophrenia and autism as well
as in developmental delay, changes in brain size, and epilepsy. Highthroughput
sequencing (HTS) technologies have opened new and
exciting opportunities for CNV discovery. Huge amounts of
sequencing data are emerging for the study of psychiatric disorders.
However, the detection and analysis of CNVs from HTS data are
challenging. Some of the statistical challenges stem from the
experimental biases in HTS that have direct effects on pairing the
reads and estimating read depth. We present a novel statistical
method and software tool for CNV discovery from read-­‐‑depth (RD)
analysis of genome sequencing.
Methodology: Our method uses a hidden Markov model and
negative binomial regression framework to identify copy number
gains and losses while simultaneously accounting for the effects of
multiple confounding factors. Known confounding factors are
corrected explicitly (e.g., GC content and mappability). Unknown
experimental biases, such as ambiguous reads mapped to the regions
due to misalignment and sequencing errors, are tolerated by the overdispersion
parameter of the negative binomial distribution. Given the
predicted CNV regions, additional refinements are carried out by
applying a hidden semi-Markov model and by integrating paired-end
mapping, split-read mapping, and breakpoint-junction analysis to
redefine CNV-boundaries.
Results: To calibrate our method, we analyzed the high-coverage
data from the 1000 Genomes Project (1000GP) and compared the
CNV calls to a gold standard CNV dataset and to the extensive
validation performed by 1000GP. Our read-depth-based integrative
method is complementary to split-­‐‑read and read-­‐‑pair approaches. We
have obtained whole genome sequencing data from two cases with
schizophrenia sequenced at 40X coverage and will apply our method
to these data.
Conclusions: Our method has been efficiently implemented in C++.
Due to the highly parallel structure of the problem, we plan to
parallelize the analysis process to further accelerate the computation.
A user-friendly implementation of the complete analytic protocol will
be freely available.

PP49 QUANTITATIVE TRANSCRIPTOME SEQUENCING
REVEALS ALTERED PRESYNAPTIC VESICLE
TRAFFICKING AND MYELINATION IN THE TEMPORAL
CORTEX IN SCHIZOPHRENIA
J. Wu(1,2,3), P. Tooney(1,2,3), X. Wang(2,3), M. Cairns*(1,2,3)
1. Schizophrenia Research Institute 2. University of Newcastle 3.
Hunter Medical Research Institute
*murray.cairns@newcastle.edu.au
Introduction: While genome wide transcription analysis of
postmortem tissue using hybridization has provided important insight
into the neuropathology of schizophrenia, it represents a restricted
view of disease-associated transcriptional variation based on a
predetermined probe set. Deep sequencing technology now provides
the opportunity to make an un-biased analysis of mRNA transcription
and processing down to nucleotide resolution. In this study we used a
sequencing approach to investigate whole genome expression in
postmortem cortical grey matter from the superior temporal gyrus
(BA22) in 9 cases of schizophrenia and 9 non-psychiatric controls
matched for gender, age, brain hemisphere, postmortem interval, and
pH.
Methodology: The data was generated from 76 bp reads using an
Illumina Genome Analyser II, and aligned using TopHat, arranged
into exons and spliceoforms using Bowtie and digitally quantified
using Cufflinks software.
Results: The output, amounting to more than 38 Gb of sequence,
revealed significant alteration of gene expression including many
genes and pathways previously shown to be associated with
schizophrenia. Genes in the presynaptic vesicle trafficking and
myelination pathways were particularly striking and broadly
consistent with previous analysis using microarray. There was also
substantial overlap with target genes predicted to interact with
microRNA shown previously to be differentially expressed in this
tissue 1 . We also identified differences in the abundance of
transcriptional and splicing isoforms between the groups, which
could have important functional significance for schizophrenia. We
are currently investigating functionally significant coding and noncoding
polymorphism in the context of transcripts altered in
schizophrenia.
Conclusions: This analysis provides a rich source of data, with detail
way beyond the scope of hybridization, that will continue to provide
clues about the underlying causes of cortical gene dysregulation in
schizophrenia as new questions arise.
1. Beveridge NJ, Gardiner E, Carroll AP, Tooney PA, Cairns MJ.
Schizophrenia is associated with an increase in cortical microRNA
biogenesis. Molecular Psychiatry 2010 15(12): 1176-1189.
92
PP50 NEXT-GENERATION SEQUENCING OF KNOWN AND
PUTATIVE SUSCEPTIBILITY GENES FOR
SCHIZOPHRENIA AND AUTISM SPECTRUM DISORDERS
TO DETECT RARE HIGH-PENETRANT RISK VARIANTS
D. Morris*, S. Furlong, E. Kenny, P. Cormican, C. Fahey, R. Anney,
G. Donohoe, A. Corvin, L. Gallagher, M. Gill
Trinity College Dublin
*morrisdw@tcd.ie
Introduction: Schizophrenia (SZ) and autism spectrum disorders
(ASD) are complex neurodevelopmental disorders that share certain
phenotypes including cognitive deficits and some behavioural
characteristics. Such similarities suggest that these disorders may
share an underlying pathology and thus may share some genetic risk
variants. This study involves next-generation sequencing of the
exonic regions of 215 potential susceptibility genes in an Irish sample
of 150 cases of ASD, 300 cases of SZ and 300 controls, in order to
identify single nucleotide polymorphisms, indels and structural
variants contributing to one or both disorders.
Methodology: A multiplex target enrichment method is used
whereby DNA samples are multiplexed together using DNA
indexes/barcodes and enriched for the exonic regions of these genes
using the Agilent SureSelect target enrichment method. This is
followed by 80bp paired-end sequencing in a single lane of an
Illumina GAII. Gene selection comprised of five categories: 1)
Interactors of NRXN1, 2) Interactors of DISC1, 3) Genes within the
Glutamate Receptor Complexes NMDA, mGluR5 and AMPA, 4)
Cell adhesion molecules and 5) Functional and Positional Candidates.
Results: Analysis of the pilot set of samples indicates that the
approach undertaken is successful with an even spread of sequence
information for 24 indexed samples per lane, >8X coverage for 84%
of target regions and overall SNP concordance with previous GWAS
data (Affymetrix 6.0) of 99.3%.
Conclusions: In addition to description of this novel sequencing
method, data will be presented on the rare variant analysis in the SZ
and ASD samples.

PP51 GENOME-WIDE ASSOCIATION ANALYSIS OF
COGNITIVE ABILITIES IN A HEALTHY NORWEGIAN
SAMPLE WITH REPLICATION IN A LARGE UK-BASED
SAMPLE
ECIP
A. Christoforou*(1), T. Espeseth(2), G. Davies(3), C. Fernandes(1),
A. Tenesa(3), N. Pendleton(4), A. Lundervold(1), S. Cichon(5), I.
Reinvang(2), V. Steen(1), I. Deary(3), S. Le Hellard(1)
1. University of Bergen 2. University of Oslo 3. University of
Edinburgh 4. University of Manchester 5. University of Bonn
*andrea.christoforou@med.uib.no
Introduction: Cognitive abilities vary greatly among individuals and
are known to be valid predictors of life outcomes, including
education and occupation. Family, twin and adoption studies confirm
that differences in cognitive abilities are heritable, with genetic
factors accounting for approximately 50% of the variance. In
addition, it is well-established that cognitive deficits are shared by
common psychiatric disorders, such as schizophrenia and bipolar
disorder, and that variation in these impairments is genetically
associated with these disorders. Thus, understanding the genetic
factors underlying cognition may help to elucidate the mechanisms
underlying psychiatric illness. To that end, we have undertaken a
genome-wide approach of a well-characterised, homogeneous sample
of healthy adults, the Norwegian Cognitive NeuroGenetics (NCNG)
sample, with replication in the larger, well-characterised Cognitive
Ageing Genetics in England and Scotland (CAGES) sample.
Methodology: We performed a genome-wide association study
(GWAS), using the Illumina HumanHap610-Quad Genotyping
BeadChip, in the NCNG (N=670), who were tested for various
neuropsychological measures of cognition. Focusing on two factors
of general intelligence – fluid (Gf) and crystallized intelligence (Gc)
– both single-marker and gene-based analyses were performed. In
silico replication was performed using the CAGES sample
(N=~3500), which was also genotyped on the HumanHap610. The
top SNPs and genes from the NCNG were directly mined and whole
genome rank correlation analyses were performed. In addition, gene
set enrichment analysis (GSEA) was applied, querying the top hits
from the NCNG dataset for enrichment of significant signal in the
CAGES dataset.
Results: We identified one genome-wide significant SNP (Gc:
P=9.82x10 -9 ) and 148 SNPs with P≤10 -4 . Preliminary gene ontology
analysis of the genes implicated by the top 1000 SNPs from the
NCNG study identified synapse organization as the top biological
process for Gf (raw P=8.00x10 -4 adjusted P=0.28) and neuron
differentiation for Gc (raw P=5.86x10 -6 adjusted P=0.0051).
Replication at the SNP level in the CAGES sample was marginal
with only 17 of the 148 SNPs meeting the nominal significance level
(P≤0.05). Similarly, negligible genome-wide correlation was
observed (Spearman's rho

PP53 EBV COPY NUMBER IN LCLS
W. Moy*(1), J. Duan(1), A. Sanders(1), J. Freda(1), J. Jacobi(1), D.
He(1), M. Collaboration(2), P. Gejman(1)
1. Department of Psychiatry and Behavioral Sciences, NorthShore
University HealthSystem and University of Chicago 2. Molecular
Genetics of Schizophrenia (MGS) Consortium
*wmoy@northshore.org
Introduction: Transformation of B-lymphocytes with EBV produces
LCLs, which are the largest renewable source of DNA for genotyping
and sequencing, e.g., the NIMH collections of LCLs at Rutgers
University Cell and DNA Repository. Furthermore, due largely to
limitations of available living brain tissue, LCLs are commonly used
as a cellular model to study the effects of genetic variation in
neurologic and in psychiatric disorders, such as for the study of gene
expression profiles (e.g., see Sanders et al. WCPG 2011 abstract for
such a study in schizophrenia). The determinants of EBV copy
number in LCLs, whether genetic or environmental (e.g., epigenetic,
transformation methods), or both, remain unknown. However, EBV
copy number (viral load) varies across LCLs and strongly influences
the transcriptional abundances of many genes (and of many other
cellular phenotypes). Circulating B-lymphocytes in most adults
(>90%) carry a latent EBV infection, though whether EBV copy
number is influenced by past infection remains unknown. Some
researchers have hypothesized that acute EBV infection may play a
role in the etiology of major psychiatric disorders, for which
definitive evidence remains unavailable. We report here a systematic
analysis of determinants of EBV copy number in LCLs.
Methodology: To detect loci influencing EBV copy number in
LCLs, we performed a GWAS using the MGS schizophrenia casecontrol
collection (European ancestry, EA, N=5,334; African
American, AA, N=2,259) with transformation site, age, sex, caseness,
and ancestry PCs as covariates.
Results: In the EA sample we found suggestive association at
12q24.21 with rs708831 (p=1.2×10 -7 ) and at 17q21.31 with
rs1043284 (p=7.8×10 -7 ), and in the AA sample at 7q33 with
rs273961 (p=4.1×10 -7 ). rs708831 is ~140 kb from MED13L
(mediator complex subunit 13-like), a widely-expressed gene
including fetal and adult brain. rs1043284 is in the 3’-UTR of
RUNDC1 (RUN domain containing 1), a gene which may play a role
as an inhibitor of the tumor suppressor gene, p53. It is known that
EBV impairs the p53 pathway, similar to other DNA tumor viruses.
We note that rs273961 is in an intronic region of CREB3L2 (cAMP
responsive element binding protein 3-like 2), a gene involved in
protein trafficking (ER à Golgi). We found a significant association
with transformation site (p

PP55 CASE-CONTROL ANALYSIS OF BIPOLAR
DISORDER GENETICS USING EXOME SEQUENCE
CAPTURE DATA
J. Parla*(1), I. Iossifov(1), D. Lewis(1), S. Mavruk(1), M.
Pirooznia(2), F. Goes(2), P. Zandi(2,3), R. Karchin(4), J. Potash(2),
W. McCombie(1)
1. Cold Spring Harbor Laboratory 2. Department of Psychiatry, Johns
Hopkins School of Medicine 3. Department of Mental Health, Johns
Hopkins Bloomberg School of Public Health 4. Department of
Biomedical Engineering and Institute for Computational Medicine,
Johns Hopkins University
*parla@cshl.edu
Introduction: Bipolar disorder I (BP) is a major mental illness with a
significant genetic component, as demonstrated by family, twin, and
adoption studies. Molecular investigation into the genetics of BP has
included linkage analyses, and, more recently, several genome-wide
association studies (GWAS). While GWAS has yielded a couple of
genome-wide significant results, the “missing heritability” problem
suggests that other approaches are necessary to uncover BP
susceptibility variants. We are applying exome capture and
resequencing towards finding rare genetic variants that contribute to
BP.
Methodology: The initial stage of case-control data production
involved 105 BP I probands and 51 matched controls. This study was
enabled by SeqCap EZ Human Exome SR v1 kits (26.2 Mb target
size) from NimbleGen and advanced DNA sequencers from Illumina.
Each exome capture sample was initially sequenced on one lane of a
paired-end 76-cycle GAIIx run, with up to one lane of additional
sequencing if the initial data were not enough to provide
approximately 80% of the exome target at 20X sequencing depth.
The sequence data generated from each capture were analyzed using
a bioinformatic pipeline consisting of the alignment program BWA,
the SAMtools software package, and custom scripts.
Results: On average, 36.5 million pass-filter sequence read pairs (5.5
billion bases) were produced per captured sample, with 99.7% of
bases attributed to sample DNA (rather than sequencing adapter),
93.5% of read pairs properly mapped with unique genomic
coordinates, 57.5% of properly mapped read pairs mapped to exome
probe sequences, and 31.3% of the total input pass-filter sequence
data mapped to the exome target. The sequence data provided 81.6%
of the exome covered at 20X depth, 13,694 coding SNPs, 7,545
synonymous SNPs, and 6,149 nonsynonymous SNPs per sample, on
average. From these results, we have identified 275 genes with
possibly damaging, non-synonymous SNPs found in cases, but not in
controls. There also appears to be an enrichment of non-synonymous
SNPs in BP GWAS-identified genes in cases compared to controls.
Conclusions: We generated significant exome coverage for 156 casecontrol
samples and called several thousand coding variants per
individual, including some found in cases but not controls. Additional
case-control analyses will be completed soon. We have recently
initiated a custom capture design with NimbleGen that will include
their updated exome target (v2), along with the promoters and exons
of 1,517 genes that encode post-synaptic proteins and genes
identified in BP GWAS. The integration of synapse genes will allow
us to investigate the relationship of synapse function to BP.
95
PP56 NO EVIDENCE OF EXCESS REGIONS OF
HOMOZYGOSITY IN SCHIZOPHRENIA OR BIPOLAR
DISORDER
J. Pallesen*(1), J. Grove(1,2), D. Demontis(1), N. Lassen(1), L.
Foldager(2), M. Hollegaard(3), C. Pedersen(4), T. Ørntoft(5,6), M.
Didriksen(7), D. Hougaard(3), C. Wiuf(2), P. Mortensen(4), O.
Mors(8), A. Børglum(1,8)
1. Inst. of Biomedicine, Depts. of Human Genetics 2. Bioinformatics
Research Centre 3. Dept. of Clinical Biochemistry and Immunology,
Statens Serum Institut 4. National Centre for Register-based Research
5. Dept. of Molecular Medicine 6. AROS Applied Biotechnology A/S
7. Synaptic Transmission, H. Lundbeck A/S 8. Centre for Psychiatric
Research, Aarhus University Hospital
*jonatanpallesen@hotmail.com
Introduction: Regions of homozygosity (ROHs) are stretches of
DNA sequence where each location contains two identical alleles.
ROHs are caused by extended haplotypes, and are hypothesized to be
indicative of positive selection pressure. The presence of ROHs has
been found associated to a number of diseases and traits, among
others late onset Alzheimer’s disease and schizophrenia (SZ). Lencz
et al (PNAS, 2007) defines a common ROH (cROH) as a region
where a preset number of individuals share 100 or more homozygous
calls. In a SZ case-control study they found an association between
ROHs and SZ, with nine cROHs being individually more frequent in
cases than in controls, and cROHs being more frequent overall in
cases compared to controls. A different study by Vine et al (Psychiatr
Genet, 2009) applied the same method to a bipolar (BP) data set, and
found no significant association. We apply here the methods used in
those studies to a different SZ data set and a different BP data set.
Methodology: Subjects in the SZ study were obtained from the
Danish Newborn Screening biobank.Genotyping was performed
using an Illumina Human 610-quad beadchip. After quality control,
the study included 1,774 individuals (888 cases, 888 controls) and
541,148SNPs. Subjects in the BP study was obtained from WTCCC.
Genotyping was performed using theGeneChip 500K Mapping Array
Set (Affymetrix chip). After quality control, the study included4,806
individuals (1,868 cases, 2,938 controls) and 402,910 SNPs.ROHs
and cROHs were defined as in the mentioned publications. Analyses
were carried out using plink and Python code produced by the
primary author.
Results: With the appropriate cROH threshold, we found a number
and coverage of cROHs similar to that of the two previous studies.
For neither SZ nor BP, did we find any individual cROH with a
significant difference in the distribution between cases and controls
after adjusting for multiple testing, nor were there any systematic
majority of either cases or controls among the top results. Seven out
of the nine cROHs that were found by Lencz et al to be significant for
SZ, were also present in our SZ study, but none of them differed
significantly in the distribution between cases and controls. We did
not replicate the finding of overall greater number of cROHs among
cases, but instead found a significant overall greater number of
cROHs among controls (P = 0.0022). In BP, we found as Vine et al
that there was no significant difference in the overall number of
cROHs among cases compared to controls.
Conclusions: We could not replicate the results of Lencz et al of
individual cROHs being associated to SZ. But we did find a
significant difference in the overall number of cROHs, although in
contrast to Lencz et al we found them to be more frequent in controls.
We replicated the results of Vine et al of no difference in the overall
number of cROHs in BP. The results suggest that cROHs do not have
a large role to play in the case of BP. But there are indications that
the distribution of cROHs is different in SZ patients.

PP57 GENOME-WIDE ASSOCIATION STUDY OF
MIGRAINE AND COMORBID DEPRESSION
M. Rivera*(1), Z. Samaan(2), S. Cohen-Woods(1), G. Breen(1), R.
Investigators(1), C. Lewis(1), I. Craig(1), P. McGuffin(1), A.
Farmer(1)
1. MRC SGDP Centre, Institute of Psychiatry, King's College
London 2. Department of Psychiatry and Behavioural Neurosciences,
McMaster University
*margarita.rivera_sanchez@kcl.ac.uk
Introduction: Migraine is a common neurological disorder that is
highly comorbid with psychiatric disorders such as depression.
Epidemiological and clinical studies have consistently reported a
positive correlation between depression and migraine. These studies
show a higher risk for depression among individuals with migraine
and also a higher risk for migraine among individuals with
depression. The aim of this genome-wide association study (GWAS)
is to identify genetic variants that contribute to the development of
migraine comorbid with depression.
Methodology: The sample consists of approximately 2,500
depressive cases and healthy controls sourced from the Depression
Case-Control (DeCC) study and the Depression Network (DeNT)
study. ICD-10 depression diagnoses were made using the SCAN
interview. The controls were screened for lifetime absence of any
psychiatric disorders. Within each group, the different categories of
migraine were established using the Structured Migraine Interview
(SMI) designed using International Headache Society criteria.
Depression cases and controls were genotyped using the Illumina
HumanHap610-Quad BeadChip by the Centre National de
Génotypage.
Results: After applying stringent quality control criteria for missing
genotypes, departure from Hardy-Weinberg equilibrium, and low
minor allele frequency, logistic regression corrected for population
stratification was performed to test for association to migraine in the
whole sample, that is in depressive cases, and controls. Strong
evidence for association was found for several SNPs located on
chromosomes 2, 3 and 17 (p=7.6 x10 -6 , p=5.6 x10 -6 , p=6.5 x10 -6 ,
respectively).
Conclusions: This is the first GWAS study investigating the genetic
contribution to migraine comorbid with depression in a large clinical
sample of depressive patients and controls individuals. This study has
identify evidence for association with several genetic variants that
merit further investigation.
96
PP58 GENOME-WIDE COPY NUMBER VARIATION (CNV)
ANALYSIS FOR SCHIZOPHRENIA IN A LARGE
ASHKENAZI COHORT
S. Guha*(1), J. Rosenfeld(1), A. Malhotra(1,2,3,4,5), A. Darvasi(6),
T. Lencz(1,2,3,4,5)
1. Department of Psychiatry, Division of Research, The Zucker
Hillside Hospital Division of the North Shore – Long Island Jewish
Health System 2. Center for Psychiatric Neuroscience, The Feinstein
Institute for Medical Research 3. Department of Psychiatry and
Behavioral Science, Albert Einstein College of Medicine of Yeshiva
University 4. Department of Psychiatry, Hofstra University School of
Medicine 5. Dept. of Molecular Medicine, Hofstra University School
of Medicine 6. Department of Genetics The Institute of Life Sciences,
The Hebrew University of Jerusalem
*sauravguha@gmail.com
Introduction: Copy number variations (CNVs), are recognized to
contribute to normal human genomic variability and also associated
with the risk of human diseases. Recent genome-wide studies have
provided evidence that CNVs may also be associated with
schizophrenia and other psychiatric disorders. Ethnically
homogeneous founder population may increase power for detection
of rare and common CNVs associated with human disease.
Methodology: To identify copy number variations (CNVs) that
increase the risk of schizophrenia, we performed a whole-genome
CNV analysis on a cohort of 1233 schizophrenia and schizoaffective
cases and 2279 controls drawn from the Ashkenazi Jewish (AJ)
population from Israel. Ethnically homogeneous samples were
selected from a larger AJ cohort and genotyped for 1.4 million probes
using Illumina HumanOmni1-Quad arrays. After stringent quality
filtering for both samples and markers, we performed PCA with AJ
specific AIMs and MDS correction in PLINK to correct for any
population stratification effects.
Results: Currently, we are analyzing all the samples after QC were
using multiple CNV calling algorithms to overcome the false positive
CNV calls, often associated with CNV analysis. The final CNV
identification would be based on common consensus calls from all
the used algorithms with minimum 5 probes and 20 kb in size and
quality score for the respective algorithms.
Conclusions: The resulting CNV calls would be subsequently
analyzed at PLINK for rare and common CNVs associated with
schizophrenia.

PP59 GENOME-WIDE ANALYSIS OF RARE COPY
NUMBER VARIANTS IN ATTENTION
DEFICIT/HYPERACTIVITY DISORDER (ADHD)
CONFIRMS THE ROLE OF RARE VARIANTS AND
IMPLICATES DUPLICATIONS AT 15Q13.3 IN DISEASE
ETIOLOGY
B. Franke*(1), N. Williams(2), E. Mick(3), S. Faraone(4), O.
IMAGE II Consortium(4)
1. Departments of Human Genetics and Psychiatry, Donders Institute
for Brain, Cognition and Behavior, Radboud University Nijmegen
Medical Centre 2. Department of Psychological Medicine, School of
Medicine, Cardiff University 3. Department of Psychiatry, Harvard
Medical School, Massachusetts General Hospital 4. Departments of
Psychiatry and of Neuroscience and Physiology, State University of
New York Upstate Medical University
*b.franke@antrg.umcn.nl
Introduction: ADHD is a common neurodevelopmental psychiatric
disorder with a strong impact on patients’ lives. ADHD is highly
heritable, but due to its multifactorial etiology, identifying the genes
involved has been difficult. Recent findings suggest that rare copy
number variants (CNVs) might be of importance for ADHD etiology.
Methodology: The current study performed a genome-wide analysis
of rare CNVs (less than 1% population frequency) larger than 100 kb
in size in a large sample of children with DSM-IV ADHD (n=896)
and controls (n=2455) from the IMAGE II study.
Results: A total of 1562 individually rare CNVs >100 kb were
observed, which segregated into 912 independent loci. Overall, the
rate of rare CNVs larger than 100 kb was increased by 1.15-fold in
the ADHD cases compared to controls (p=0.014) with duplications
spanning known genes showing 1.2 fold enrichment (p=0.01).
Moreover, CNVs identified in our ADHD cases were significantly
enriched for loci previously implicated in autism (p=0.009) and
schizophrenia (p=0.03). In accordance with a previous study, rare
CNVs larger than 500 kb showed the greatest level of enrichment
(1.28-fold) in ADHD cases compared to controls (p=0.032). Single
locus analysis revealed that a duplication on chromosome 15q13.3
showed a nominally significant association with ADHD (p=0.011)
and this was replicated in a total of 3455 ADHD cases and 11105
controls obtained from four independent cohorts from the UK, the
USA and Canada (combined p=0.0018). Exploratory analyses in a
subset of patients suggested that the presence of the duplication at
15q13.3 increases disease severity and is associated with the presence
of conduct disorder.
Conclusions: Our findings support an earlier finding of CNV
enrichment in ADHD and implicate duplications at the 15q13.3 locus
as a novel candidate risk factor for ADHD. Due to its frequency of
0.6% in the populations investigated and its relatively large effect
size (O.R.=1.94 (C.I. 1.28-2.94)), this locus could contribute
substantially to ADHD's etiology.
97
PP60 A GENOME-WIDE APPROACH TO INVESTIGATE
SCHIZOPHRENIA WITH COMORBID EPILEPSY
A. Kähler*(1,2,3), S. Akterin(2), P. Magnusson(2), S. Purcell(4,5,6),
P. Sklar(4,5,6,7), P. Lichtenstein(2), C. Hultman(2), P. Sullivan(1,2)
1. Department of Genetics, University of North Carolina 2.
Department of Medical Epidemiology and Biostatistics, Karolinska
Institutet 3. Department of Psychiatry, Oslo University Hospital -
Ulleval 4. Psychiatric and Neurodevelopmental Genetics Unit,
Department of Psychiatry, Massachusetts General Hospital and
Harvard Medical School 5. Center for Human Genetics Research,
Massachusetts General Hospital 6. Stanley Center for Psychiatric
Research, Broad Institute 7. Division of Psychiatric Genomics,
Department of Psychiatry, Mount Sinai School of Medicine
*anna_kahler@med.unc.edu
Introduction: Schizophrenia is a complex disease, with a heritability
estimate of 81%. The last three years have been a success for the field
of schizophrenia genetics, with reports of robust associations of rare
copy number variations (CNVs) and common single nucleotide
polymorphisms (SNPs). Evidence has been provided for a polygenic
architecture for schizophrenia with a risk profile significantly
predicting caseness in independent schizophrenia samples but not
non-psychiatric disorder samples. However, schizophrenia is
clinically heterogeneous, and pinpointing more homogeneous
subgroups might lead to new discoveries. There is an increased risk
for epilepsy in patients with schizophrenia and vice versa, and
specific large CNVs have been associated with risk for both diseases.
In the present study we approach the clinical heterogeneity by
assessing schizophrenia patients with and without comorbid epilepsy,
to search for genetic differences.
Methodology: A sample of 5,346 schizophrenia cases and 6,491
controls has been collected from a national epidemiological sampling
frame in Sweden. All cases were identified via the Swedish Hospital
Discharge Register, and had been hospitalized ≥2 times with a core
schizophrenia discharge diagnosis. GWAS genotyping is now
available for 4,922 subjects (Affymetrix 6.0) and genotyping will be
completed on the rest of the sample by June 2011 (Illumina Omni
Express). Subjects with comorbid epilepsy were identified based on
questionnaire data (~5% of schizophrenia cases) and were verified
using discharge and outpatient care diagnoses (ICD8-9: 345; ICD10:
G40-G41). CNV calling was performed using PennCNV. GWAS and
CNV analyses are ongoing.
Results: We will present results evaluating the hypothesis that
epilepsy defines a genetically distinct subgroup of cases with
schizophrenia. The assessment will be based on: schizophrenia risk
profile scores, CNV burden, and association analyses for specific
SNP and CNV loci.
Conclusions: In our large population-based case-control GWAS
sample we confirm that there is an increased presence of epilepsy in
patients with schizophrenia. Our sample will enable us to further
investigate the genetics of the subgroup of patients with both
disorders which might lead to new insights regarding the etiology of
schizophrenia.

PP61 INCREASED FREQUENCY OF A COMMON
DELETION IN ERBB4 IN THE IRISH STUDY OF HIGH-
DENSITY SCHIZOPHRENIA FAMILIES
E. Loken*(1), R. Elves(1), B. Webb(2), D. Walsh(3), F. O'Neill(4),
K. Kendler(1,2), B. Riley(1,2)
1. Department of Human Genetics, Virginia Commonwealth
University 2. Department of Psychiatry, Virginia Commonwealth
University 3. Health Research Board 4. Department of Psychiatry,
Queens University
*lokenek@vcu.edu
Introduction: Rare copy number variants (CNVs) (eg, in NRXN1)
and recurrent, low frequency CNVs (eg, on 22q) are associated with
schizophrenia. Common CNVs, by contrast, have not been assessed,
although there is clear potential for such CNVs to act as common,
small effect-size variants in the etiology of common complex
traits. In CNV calls from a genome-wide association study (GWAS)
of Irish multiplex pedigrees, we observed an apparent excess of a
common deletion in the first intron of ERBB4 when in affected
family members compared to unaffected ones. The total ISHDSF
sample is made of 270 families and 1,425 individuals, 854 of which
were genotyped on the Illumina 610 Quad array. This common
5,000bp ERBB4 deletion has been identified in several
populations. This is the first study of its relationship to
schizophrenia. We directly compared the frequency of this common
CNV in 1) genetically independent members of the Irish multiplex
pedigrees and population estimates and 2) Irish singleton cases
compared to Irish population controls.
Methodology: Family CNVs were called from Illumina 610 Quad
array probe intensity data using PennCNV. A population sample of
N=1320 North Americans of European descent estimated the ERBB4
CNV frequency at 4.5%. To increase the number of such samples,
independent pedigree member identity was determined by using all
possible members of the families with independent biologic
relationships. We selected 277 genetically independent pedigree
members for comparison with the population frequency and directly
assessed their copy number status by real-time PCR. Because
differences between the population frequency and the frequency
observed in our sample could be due to ethnic differences, we are
also testing the deletion frequency in an independent sample of Irish
cases and Irish controls. We used RNase P amplification for highly
accurate quantitation of DNA concentration. We called CNV
genotypes using TaqMan copy number assays from ABI and
CopyCaller Software v1.0.
Results: Preliminary validation data in the first 111 independent
family members yields a deletion frequency 10.4% compared with
4.5% in the North American population sample (chi-sq=15.17,
p

PP63 A GENOME-WIDE SEARCH FOR GENETIC
MODIFIERS OF ADAPTIVE BEHAVIOR IN MALES WITH
FRAGILE X SYNDROME
A. Kähler*(1,2,3), A. Collins(1), J. Szatkiewicz(1), M. Losh(4), D.
Hatton(5), A. Taylor(6), J. Piven(7), P. Sullivan(1,2)
1. Department of Genetics, University of North Carolina 2.
Department of Medical Epidemiology and Biostatistics, Karolinska
Institutet 3. Department of Psychiatry, Oslo University Hospital -
Ulleval 4. Department of Communication Sciences and Disorders,
Northwestern University 5. Department of Special Education,
Vanderbilt University 6. Kimball Genetics 7. Department of
Psychiatry, University of North Carolina
*anna_kahler@med.unc.edu
Introduction: Autism is a severe neurodevelopmental disorder
defined by social and communication deficits and ritualisticrepetitive
behaviors. In ~10% of cases, autism co-occurs with a
Mendelian genetic disorder such as Fragile X Syndrome (FXS). FXS
is the most frequent form of inherited mental retardation, and is
caused by loss-of-function mutations in Fragile X mental retardation
1 (FMR1). Although FXS subjects all have FMR1 mutations, the
degree of autism varies dramatically from minimal to moderate or
severe. In the present study, we use FMR1 as a “toehold” for the
identification of genetic modifiers of adaptive behavior. Given that
all subjects have the same predisposing genetic lesion, searches for
genetic modifiers influencing adaptive behaviors could be
particularly powerful as heterogeneity is minimized.
Methodology: Males with FXS were recruited from volunteer
registries. Phenotypic data were collected using the Vineland
Adaptive Behavior Scales-II (VABS), measuring adaptive behavior
skills (communication, daily living skills, socialization, and motor
skills). GWAS genotyping was conducted using Illumina 1M SNP
chips. The GWAS SNPs were partitioned into a hypothesis-driven set
consisting of SNPs in or near genes that code for molecules known to
interact with FMR1 or its protein product and a discovery set (all
other SNPs). Association tests were performed using linear
regression in PLINK with VABS as the dependent variable and age
and ancestry principal components as covariates. CNV calling was
carried out with PennCNV, and pathway analyses with Aligator.
Results: The final GWAS data set consisted of 88 FXS males and
733,183 SNPs. There were 16,178 SNPs in 519 genes encoding
molecules that interact with FMR1 or its protein product, and none of
these reached the significance level for the hypothesis-driven SNP
set. Similarly, no SNP in the discovery set reached genome-wide
significance. However, based on pathway analysis, there was a
significant enrichment of genes with small p-values in 16p11.2, a
region containing a CNV previously associated with autism and
schizophrenia. Moreover, around a third of subjects had predicted
CNVs covering regions and genes associated with autism, including a
subject with a large 16p11.2 duplication and the largest degree of
social impairment in the sample. Verification genotyping is in
progress and will be presented.
Conclusions: Based on these preliminary and as yet unverified
findings, these data may be consistent with a “two-hit” model – the
initial hit is the FMR1 mutation and phenotypes of clinical
importance are then determined by mutations elsewhere in the
genome (e.g., common variation on 16p11.2 and pathogenic CNVs).
Thus, even “simple” Mendelian disorders have unexpected
complexity in relation to behavioral outcomes.
99
PP64 A STATISTICAL METHOD FOR DETECTING RARE
VARIANTS IN PEDIGREES WITH PSYCHIATRIC
DISORDERS
Y. Shugart*(1), M. Xiong(2)
1. IRP, Stat Genomics, NIMH/NIH 2. Department of Epidemiology,
University of Texas
*kay1yao@mail.nih.gov
Introduction: The hyphothesis of common disorder rare variants
assumes that complex disorders such as psychiatric disorders are
causes by multiple rare variants (assuming MAF less than 5%) with
modest effect. These rare variants are expected to affect protein
function and many of them are missense mutations in protein coding
regions. We hypothesize that these rare variants are likely to
modulate gene expression level or change amino acids sequence, and
can sometime lead to human disorders.
Methodology: Recently, a few new statistical methods have emerged
in analyzing exome sequencing data in case-control samples. For
instance, the well-developed CMC method focus on the comparison
of number of non-synonymous alleles between cases and controls.
However, this type of approach can be applied to families data. Here
we propose a simplistic statistical method, which compares the
average of rare variants counts in affected relative pairs and unrelated
relative pairs. The estimate from each group is then weighted by
variance calculated from the IBD estimates for various types of
related pairs. Further, we use the actual IBD sharing to take into
account the dependent relatioship from multiple affected pairs within
the sample pedigree.
Results: Simulation based results indicated that our method worked
reaonably well under a variety of genetic models. Software
development is underway.
Conclusions: It is feasible to use affected relatives and unaffected
relative pairs from the same population to detect rare variants
underlying complex human disorders such as schizophrenia and
bipolar disorder.

PP65 WHOLE GENOME SEQUENCING IN LARGE
PAKISTANI FAMILIES WITH MENTAL ILLNESS
M. Ayub*(1), D. Blackwood(2), K. Mahmood(3), R. Taj(4), A.
Maclean(2), A. Mir(5), F. Naeem(6), J. Knowles(7)
1. University of Durham 2. University of Edinburgh 3. Arrahma
Hospital 4. Pakistan Institute of Medical Sciences 5. International
Islamic University 6. Lahore Institute of Research and Development
7. University of Southern California
*mohammad.ayub@tewv.nhs.uk
Introduction: Genome wide association studies have successfully
identified many genes which are likely to be associated with
Affective Disorders and Schizophrenia. However a significant
proportion of variance remains unexplained. One possible
explanation may be involvement of multiple rare variants. Over last
two years a few studies have been published which utilized either
whole genome or exome sequencing to find disease causing
mutations mainly in Mendalian disorders. This approach can
potentially be useful in families with complex disorders. Multiply
affected single families may be a useful resource for study of rare
variants utilizing whole genome sequencing.
Methodology: We have collected a number of such families from
Pakistan. In these families either Affective Disorder or Schizophrenia
is segregated in apparently Mendalian fashion. We initially
performed genome wide linkage analysis in some of these families
and found significant linkage. We are currently performing whole
genome sequencing in selected individuals in some of these families.
Results: We shall present initial findings from the sequencing data
from this study.
Conclusions: We shall explore the challenges in interpretation of
sequencing data in this context.
100
PP66 PHENOTYPING, PREVALENCE, AND GENETIC
SIGNATURE OF POSTPARTUM DEPRESSION IN THE
NESDA GWAS STUDY
S. Meltzer-Brody*(1), B. Penninx(2), I. Jones(3), P. Sullivan(1)
1. University of North Carolina at Chapel Hill 2. VU University
Medical Center 3. Cardiff University School of Medicine
*meltzerb@med.unc.edu
Introduction: Efforts to identify the genetic basis of major
depression (MDD) have proven challenging. It is possible that the
highly heterogenous nature of MDD has complicated efforts to find
biomarkers and genetic associations. Decreasing heterogeneity by
focusing on a specific sub-type of MDD offers significant promise.
Postpartum depression (PPD) is an MDD sub-type occurring within
the first 3 months postpartum and has devastating consequences for
the woman, her children and family. PPD is common with a
prevalence of 10-20% and provides a more homogenous subset of
MDD (females only, age-banded, all exposed to the same
biopsychosocial event). Objectives: To perform phenotyping for PPD
cases in the NESDA GWAS cohort study and to perform an unbiased
screen for a genetic signature of PPD.
Methodology: The parent project that supplied subjects for this
GWAS is the Netherlands Study of Depression and Anxiety
(NESDA). NESDA is an ongoing longitudinal cohort study designed
to be representative of individuals with depressive and anxiety
disorders. Initial recruitment of NESDA participants was from
09/2004-02/2007. Participants were aged 18 to 65 years at enrollment
with current DSM-IV MDD diagnosis ascertained by CIDI. Within
these studies, 1992 MDD cases had GWAS genotyping completed.
To determine PPD status, we developed a modified lifetime version
of the Edinburgh Postnatal Depression Scale (EPDS) which was
administered during the four year follow-up interview of NESDA
(09/2008-02/2011). The modified EPDS contains questions about
lifetime history of mood or anxiety changes during pregnancy and
postpartum, timing of initial onset of symptoms, and history and type
of mental health treatment. We defined a positive screen for lifetime
history of PPD based on a standard cut-off (total score >12). Based
on PPD phenotyping, we performed a hypothesis generating GWAS
of PPD based on 435,291 SNPs.
Results: In the NESDA cohort, 2396 study participants have been
phenotyped for PPD. Data analysis is currently in progress and will
be formally completed by July 2011 and ready to present in
September 2011. We will report: 1) the prevalence of lifetime history
of PPD; 2) prevalence of history of a positive screen on the EPDS; 3)
risk factors for PPD that are distinct from MDD such as age cohort
effect, marital status, SES, severity of illness, parity status, clinical
outcome, and history of trauma and abuse; 4) timing of onset of
perinatal mood symptoms (pregnancy vs postpartum); 5) GWAS
analyses based on PPD phenotyping.
Conclusions: PPD is a severe and persistent form of MDD that is one
of the most frequent complications of childbirth. Understanding the
phenotypic characteristics and risk factors that distinguish PPD from
MDD as well as elucidating the genomic signature of PPD has
important and far reaching implications that could provide insight
into trait-related vulnerabilities to MDD and potentially lead to future
prospective identification of women at risk for developing PPD.

PP67 SEQUENCING HUNDREDS OF EXOMES IN SWEDISH
SCHIZOPHRENIA PATIENTS AND CONTROLS
D. Ruderfer(1,2), M. Fromer(1,2), J. Moran(2), K. Chambert(2), P.
Lichtenstein(3), P. Sullivan(4), C. Hultman(3), P. Sklar(1,2,5), S.
Purcell(1,2)
1. Massachusetts General Hospital 2. Stanley Center, Broad Institute
3. Karolinska Institutet 4. University of North Carolina 5. Mount
Sinai School of Medicine
Introduction: Schizophrenia is common, complex disease with a
strong genetic basis. Although recent genome-wide studies have
indicated important roles for both common single nucleotide
polymorphisms (SNPs) and large, rare genic deletions and
duplications, the majority of the heritability remains unexplained.
Methodology: Next-generation sequencing (NGS) technologies can
interrogate genetic variation that has previously eluded detection in
genome-wide studies, namely rare SNPs and small
insertions/deletions. We aim to relate this class of rare genetic
variation to risk for schizophrenia by applying NGS to large,
carefully-selected samples of cases and controls. We have selected
959 samples for whole-exome sequencing from a larger samples of
over 5,000 Swedes on whom whole-genome SNP data are available.
Results: To date, we have sequenced 559 individuals at high depth,
targeting CCDS and RefSeq genes with the Agilent SureSelect target
sets. Solexa/Illumina GAII 76-base paired-end reads were aligned to
hg19 using BWA and the Picard pipeline. Mean coverage was 140x
and 97% of target bases were covered at 10x or more. Using the
Genome Analysis Toolkit (GATK) we called a total of 173,298
variant sites passing all quality-control filters, with a mean
transition/transversion ratio of 3.1. Comparison with GWAS calls at
~5000 exonic sites shows very high genotypic concordance
(>99.9%). Per individual, ~94.4% of variants with a non-reference
genotype were previously observed in the 1000 Genomes Project.
Using a second variant-calling approach (Samtools), 87% of sites
overlapped with GATK calls; the consensus set demonstrated a
higher Ti/Tv (3.23) than the calls specific to a single method (1.66
and 1.68 for GATK and Samtools, respectively).
Conclusions: We have developed PLINK/Seq, an analytic toolset to
handle downstream QC and association analysis of the genetic
variation data from NGS studies. Genotype-phenotype association
analysis is ongoing, at the single variant, gene and gene-set
(pathway/network) levels. The main focus of this presentation will be
to present the primary association results from this study and discuss
the some of the analytic challenges inherent in these studies.
101
PP68 MICRODELETIONS OF PROXIMAL 15Q11.2
ASSOCIATED WITH SCHIZOPHRENIA
T. Wassink*, D. Rudd, M. Axelsen, N. Andreasen
University of Iowa
*thomas-wassink@uiowa.edu
Introduction: Genomic copy number variation has been found to
underlie a significant number of cases of neuropsychiatric disorders.
Interestingly, most neuropsychiatric CNVs increase risk for multiple
disorders. Chromosome 15q11-13 is emblematic of this, with CNVs
across the interval being associated with Prader-Willi/Angelman
syndrome, autism, and other psychiatric phenotypes. The region
contains four canonical segmental duplications that predispose to
CNV formation, but only recently have disease-associated CNVs
been reported between the two most proximal breakpoints (BP1 and
BP2). We report here a CNV study of schizophrenia in which we
identified multiple 15q11.2 BP1-BP2 deletions. These findings are
supplemented by additional cases from our clinical cytogenetics
laboratory.
Methodology: 181 individuals with schizophrenia and 69 controls
were studied with the Affymetrix Array 6.0. Array data was scanned
for CNVs using two software programs: CNAG and Genotyping
Console. CNVs identified by both programs were carried forward for
analysis. Participants had also undergone extensive neuropsychiatric
testing and structural brain magnetic resonance imaging. CNVs were
compared between affecteds and controls and also with CNVs
recorded in the Database of Genomic Variants. CNVs unique to
schizophrenia were confirmed by qPCR and were then examined for
relationships with our various quantitative phenotypic measures.
Results: Amongst the numerous CNVs that were called, we
identified three schizophrenia cases with 15q11.2 BP1-BP2 deletions;
these have not been previously reported in schizophrenia. These cases
were supplemented by findings from our clinical cytogenetics
laboratory. Using the Nimblegen 385,000 probe array, we identified
two individuals with both 15q11.2 and 22q11 deletions. One of these
had childhood onset schizophrenia, while the other was diagnosed
with developmental delay. Examination of quantitative phenotypic
data from these individuals identified numerous interesting brain and
cognitive features.
Conclusions: We report a high rate (3/181=1.7%) of 15q11.2
deletions in individuals with schizophrenia. This CNV, like others
associated with neuropsychiatric phenotypes, appears to underlie
multiple disorders. The CNV may also be associated with distinct
brain and cognitive features.

PP69 PARENT OF ORIGIN EFFECT (POE) ANALYSIS OF
SEROTONERGIC AND NORADRENERGIC
POLYMORPHISMS IN MAJOR PSYCHOSES PATIENTS
WITH SUICIDAL BEHAVIOUR
C. Teo, C. Zai, J. Strauss, J. Kennedy, V. De Luca
CAMH
Introduction: Suicidality is a major health concern worldwide
particularly in major psychoses patients. Attempted suicide is
familiar. There is strong neurobiological evidence showing that
serotonergic and noradrenergic dysfunction is implicated in suicidal
behaviours.
Methodology: By the mean of ETDT and QTDT, we performed a
POE analysis on 471 families and we analyzed six genes in regards of
paternal and maternal transmissions. Then we investigated
polymorphisms in serotonergic and noradrenergic genes, considering
suicidal behaviour severity and as dichotomous phenotype (presence
of suicide attempt).
Results: The six polymorphisms (HTTLPR, rs25531, VNTR-2,
COMT rs4680, TH tetranucleotide repeat and TPH2 rs 1078941)
were not associated with suicide in paternal and maternal
transmissions. On the other hand, the analysis of the POE markers in
the adrenergic and serotonergic genes revealed that the TH allele 6
tended toward high severity in suicidal behaviour (p=0.060).
Conclusions: The marginal finding of association between TH and
severe suicidal behaviour are convergent with previous reports. On
the other hand, our sample does not have enough power to exclude
the other polymorphisms investigated as major candidate for
suicidality in major psychoses.
102
PP70 SEQUENCING BASED COMPREHENSIVE GENOME
AND TRANSCRIPTOME ANALYSES OF
VELOCARDIOFACIAL SYNDROME
A. Urban*(1), Y. Zhang(2), X. Zhu(1), D. Levinson(1), S.
Weissman(2)
1. Stanford University School of Medicine 2. Yale University School
of Medicine
*aeurban@stanford.edu
Introduction: Velocardiofacial syndrome (VCFS) is a relatively
common genomic disorder, typically caused by the heterozygous
deletion of 3 million basepairs of genomic DNA sequence on
chromosome 22q11. There are various developmental defects
including neurodevelopmental disorders such as early onset
schizophrenia, autism spectrum disorders (ASD) and learning
disabilites; however, the combinations and severity of symptoms vary
widely between patients with no clear genetic basis to such
variability, and for most symptoms there is no clear candidate gene.
Earlier [Urban, Korbel et al., PNAS 2006], we developed very-high
resolution array-CGH and used it to determine the exact breakpoints
of a panel of VCFS deletions, even in regions of segmental
duplication (SD). We discovered that even ‘typical 3 Mbp’ deletions
can differ in their endpoints by up to several hundred thousand bp in
length, affecting the copy number of many genes between patients.
Then we developed a method to use the new massively parallel
sequencing platforms (2 nd -generation sequencing, “next-generation
sequencing”) for the mapping of structural variation in the human
genome (paired-end mapping, PEM, now a standard component of
high throughput human whole-genome sequencing) [Korbel, Urban,
Affourtit et al., Science 2007]. We found hundreds of small to
medium size sequence variations in the normal human genome. Many
of those are in functionally relevant regions genome wide – and also,
additional smaller sequence variants are enriched in 22q11.
Methodology: These findings point to several genomic constellations
as possible modifiers of the main 3 Mbp deletion on chromosome
22q11: difference in deletion endpoints, small sequence variants
within the deletion region on the non-deleted chromosome, and
sequence variation genome wide. Here we report on multi-level
genomics analyses of VCFS using 2 nd -generation sequencing
(Illumina HiSeq 2000). We have sequenced the genomes of a panel
of cell lines from VCFS patients (paired-end, 4x or deeper genomic
coverage) and catalogued their genomic sequence variants from 1 bp
to several hundreds of kbp in size. For the same cell lines as well as
for controls we carried out very deep RNA-Seq analysis (up to 100
million mapped 2x100bp paired-end constructs per cell line
transcriptome). These data allow us to correlate with very high
accuracy the effects on gene expression patterns of both the copy
number changes caused by the main deletion and the additional,
patient specific, genomic sequence variants. Results: We observe
multiple small sequence variants, in the non-deleted 22q11 regions as
well as genome-wide, with some variants potentially affecting loci of
functional significance. The gene expression patterns show evidence
of gene dosage compensation for some genes as well as under- or
over-compensation for others. The mechanisms controlling such
effects will have to be studied in detail in follow-up work.
Conclusions: 2 nd - generation sequencing technologies allow the
analysis of the genetic and molecular etiology of complex
neurodevelopmental disorders with a strong genomic contribution, at
the level of resolution and the degree of comprehensiveness that will
most likely be necessary to unravel the network of molecular
interactions leading to the phenotype.

PP71 MULTIPLE NOVEL SMALL RNAS ASSOCIATED
WITH SCHIZOPHRENIA FROM MASSIVELY PARALLEL
SEQUENCING FROM PREFRONTAL CORTEX
C. Jeffries*(1), D. Perkins(2)
1. UNC Eshelman School of Pharmacy, Renaissance Computing
Institute 2. Department of Psychiatry
*clark_jeffries@med.unc.edu
Introduction: Altered regulation of gene expression is emerging as
pivotal to schizophrenia pathology. Discovery of small, noncoding,
regulatory RNAs has ushered in a new era of genomics, with
microRNAs (miRNAs) the first major class; several groups have
reported altered miRNA expression in schizophrenia. Numerous
other small RNA classes have been recently discovered, some
seemingly arising from folded RNA hairpins and processed in a
miRNA-like manner
Methodology: In order to discover novel potentially regulatory
RNAs involved in schizophrenia we used Illumina small RNA
sequencing to interrogate total RNA from the post-mortem prefrontal
cortex of ten schizophrenia and ten unaffected individuals from the
Stanley RNA collection. After sample processing we compared
unique reads against a library of 1222 human miRNAs, 182 viral
miRNAs, and 579 other noncoding small RNAs
Results: We compared the expression of the 100 most highly
detected probes (in average >80 reads per sample) between groups.
With a false discovery rate of .05, we found 14 small RNAs
differentially expressed in schizophrenia compared to unaffected
subjects, with an expected value of 5. Of the 14, 10 were miRNAs
and 4 other small RNAs
Conclusions: About a third of the most differentially expressed
probes represented miRNAs, some already identified as associated
with schizophrenia (e.g. miR-132). We report for the first time small
RNAs other than miRNAs that also distinguish schizophrenia,
anomalous levels of which might be manifestations of the disorder
103
PP72 ALTERED GENE EXPRESSION IN BIPOLAR I
PATIENTS (WITH AND WITHOUT PSYCHOSIS)
J. Neary*(1), D. Glahn(2), M. Zlojutro(1), T. Dyer(1), J.
Blangero(1), M. Carless(1)
1. Texas Biomedical Research Institute 2. Yale University School of
Medicine
*jneary@sfbrgenetics.org
Introduction: Bipolar disorder, a mood disorder delineated by
drastic swings between high and low mood states, is estimated to
manifest in 1-3% of the general population. However, close relatives
of bipolar individuals are 10-20x times more likely to develop either
depression or bipolar disorder, indicating significant heritability. Full
understanding of the developmental mechanisms involved has thus
far been hindered by the variability of clinical symptoms as well as
associated genetic complexity. Here we focus on gene expression
changes associated with bipolar I disorder (BPI) which is defined by
at least one manic episode, with or without depression.
Methodology: In our Genetics of Bipolar Disorder Study, we are
presently collecting and associating neuroanatomic (MRI) data,
neurocognitive data, and lymphocyte-derived RNA for 325
individuals: 130 affected with BPI (65 with history of psychosis),130
unaffected same-sex siblings and 65 unrelated controls. Here we
report the results of genome-wide transcriptional profiles for the first
30 BPI patients (15 with psychosis, 15 without), 25 unaffected
siblings and 15 control subjects. For genes demonstrating a >5-fold
difference in expression, we utilized Ingenuity Pathway Analysis.
Results: In BPI patients versus controls, we found significant overrepresentation
of genes involved in microglia cell binding
(p=5.43x10 -3 ), including APP, IFNG, TNF and TNR. These results
augment other reports linking microglial dysfunction to the
manifestation of psychiatric disorders. Further analysis of BPI in
psychotic versus non-psychotic BPI patients also indicated overrepresentation
of genes involved with excretion of nitrates, release of
norepinephrine (NE), and release of reactive oxygen species (AGT,
CCL24, HTR2A, IFNG, SST and TNF, p=7.64x10 -3 ). While
pathways involving NE have been previously linked to psychosis and
cognitive function, pathways involving reactive oxygen species may
represent a potentially novel target for further study and therapeutic
intervention.
Conclusions: Here we present analyses of initial data generated by
the Genetics of Bipolar Disorder study, which is still in progress. We
are presently analyzing collected neuroanatomic and neurocognitive
data, as well as miRNA transcripts and epigenetic markers for 325
people in order to identify genes implicated in the development of
BPI-related endophenotypes.

PP73 SYNAPTOMEDB: AN ONTOLOGY-BASED
KNOWLEDGEBASE FOR SYNAPTIC GENES
M. Pirooznia*(1), T. Wang(2), D. Avramopoulos (2), D. Valle(2), G.
Thomas(3), R. Huganir(3), P. Zandi(4), J. Potash(1)
1. Department of Psychiatry and Behavioral Sciences, Johns Hopkins
University 2. McKusick-Nathans Institute of Genetic Medicine,
Johns Hopkins School of Medicine, Johns Hopkins University 3.
Solomon H. Snyder Department of Neurocience, Johns Hopkins
University 4. Department of Mental Health, Johns Hopkins
Bloomberg School of Public Health, Johns Hopkins University
*mpirooz1@jhmi.edu
Introduction: The synapse is the fundamental structure for brain
function through its role in connecting neurons into circuits. Over the
past decade, the number of identified synaptic proteins has increased
by ten fold, and the synapse has been proposed as an excellent
candidate for large-scale studies such as second-generation
sequencing. As a result, there is a need for a comprehensive resource
to integrate information about synaptic proteins and the
corresponding genes (the “synaptome”) from multiple heterogeneous
sources. Here, we present an integrated database to retrieve, compile,
and annotate genes encoding components of the synapse including
neurotransmitters and their receptors, adhesion/cytoskeletal proteins,
scaffold proteins, transporters, and others.
Methodology: We compiled the human synaptome protein list from
all published proteomics studies, including literature reviews, from
2004 to 2010, as well as publicly available databases, for proteins in:
postsynaptic, presynaptic, presynaptic active zone, and synaptic
vesicle sites. We annotated the synaptome genes based on RefSeq
(GRCh37/hg19), supplemented by data from UCSC (hg19) to
identify human orthologs, their descriptions, and mapping
data. Redundant genes were removed from the list to generate a
unique gene set for the human synaptome. We then further annotated
these genes by querying 42 databases covering all aspects of biology,
including genes, proteins, pathways and other biological concepts.
Results: We assembled a list of genes (n=1885) that encode all
known proteins of the synapse. This is comprised of 575 genes
encoding proteins in the presynaptic nerve terminal and active zone,
107 from the synaptic vesicles, and 1755 from the postsynaptic
density (there is some overlap between categories). The list includes
strong candidates for bipolar disorder, such as ANK3, for major
depression, such as GRM7, for schizophrenia, such as PDE4B, and
for autism, such as SHANK3. We have developed a database with a
web front application resource, called SynaptomeDB, to integrate the
various and complex data sources for these synaptic genes. Current
developments in the project are freely available at:
http://psychiatry.igm.jhmi.edu/SynaptomeDB/
Conclusions: A synaptome-based strategy for psychiatric research is
valuable because there is evidence for synaptic proteins playing a role
in psychiatric disorders, and because these proteins represent the
most “druggable” targets for pursuit of novel therapies. Our
application will further research in this area both in its current form
and with additional modifications that will include incorporating
variation data from the 1000 Genome Project and adding links to
function based on GO and pathways.
104
PP74 MUTATION Y317X OF SLC6A8 GENE IS A POSSIBLE
POLYMORPHISM PRESENT IN PATIENTS WITH MENTAL
RETARDATION OF PSYCHIATRIC HOSPITAL "DR.
SAMUEL RAMIREZ MORENO”
C. Jiménez Z*(1), M. López N(1,2), R. Castro R(2), M. Martínez
G(3), A. Miliar G(3)
1. Secretaria de Salud 2. Instituto de Salud del Estado de Mexico 3.
Instituto Politecnico Nacional
*carlosajz@msn.com
Introduction: Mental disorders account for 12% of the global burden
of all diseases. Mental retardation (MR) is one of them and is defined
as a disorder characterized by impairment of intellectual capacity
which is below the average (IQ 70 or lower), with an age of onset
before or equal to 18 years and concurrent deficits or inadequacies in
adaptive functioning. Among the causes of MR, 30% seems to be
genetic (chromosomal, monogenic and multifactorial) and 15% has
been attributed to environmental factors (such as birth asphyxia and
infections). The rest of cases (over 50%) have an unknown etiology,
although the Human Genome Project recently completed provides
information on new mutations in genes responsible for the
appearance of this disability, is necessary the studies about this
disease. In the same types syndromes, have been described cerebral
creatine deficiency, due to inborn errors of metabolism that include
two autosomal recessive disorders that affect the biosynthesis of
creatine, this has been linked to various mutations from SCL6A8
gene, including the Y317X.
Methodology: Genomic DNA was obtained from 110 patients by
establishing a database. Although HybeProbe type probes were
genotyped each sample and sequenced to corroborate some of the
genotyping results. Was performed the statistical analysis of data
derived from medical, psychiatric and nutritional diagnosis, as well
as serum glucose, cholesterol, triglycerides, sodium, between others.
Results: After performing the genotyping of the Y317X mutation in
the DNA of 110 patients was not observed allelic variant but we
could identify a different variation to the sequence reported in
GeneBank confirmed by sequencing. On the other hand could not be
correlated with other parameters obtained from the patients, but the
study population showed no alterations in metabolic rate over 50%
were in normal weight ranges. It was also observed different degrees
of mental retardation.
Conclusions: The Y317X mutation in the SLC6A8 gene reported in
other populations and associated with mental retardation is not
present in the patients of the psychiatric hospital "DR. SAMUEL
RAMIREZ MORENO. The same patient population allele has a
change of C/T so far not reported in other populations. There are
different degrees of mental retardation in the study subjects but does
not correlate with metabolic and anthropometric variables.

PP75 REDUCED FUNCTIONAL VARIATION AMONG
NERVOUS SYSTEM GENES: IMPLICATIONS FOR
GENETIC DISEASE ARCHITECTURE
J. Freudenberg*(1), P. Gregersen(1), Y. Freudenberg-Hua(2)
1. Center for Human Genetics and Genomics Feinstein Institute for
Medical Research 2. Center for Human Genetics and Genomics
Feinstein Institute for Medical Research 3. Department of Psychiatry,
Northshore LIJ Healthsystem
*jan.freudenberg@nslij-genetics.org
Introduction: We notice that human genetic studies have identified
more loci that cause monogenic nervous system than monogenic
immune system diseases. On the other hand, relatively few
susceptibility genes for complex neuropsychiatric disorders are
unambiguously established, whereas far more solidly associated loci
exist for immunological disorders. Understanding the genetic
architecture causing these differences can improve the design of
future studies.
Methodology: Therefore, we evaluate the patterns of coding single
nucleotide variants (SNVs) among candidate genes with roles in the
immune system and the nervous system, using a published diploid
genome sequence generated by traditional Sanger technology and 200
published exomes of Danish individuals generated by next generation
sequencing.
Results: In both datasets, we find that nonsynonymous variants
(nsSNVs) are significantly less frequent in nervous system genes,
despite their longer sequences. This applies both to candidate genes
defined by their specific expression pattern and defined by their
functional annotations. Based on the observed ratio between nsSNVs
per nonsynonymous site (nsSite) and synonymous SNVs per
synonymous site, we subsequently estimate that nervous system
genes are composed of more strongly deleterious nsSites, which may
contribute to more monogenic disease manifestations. In addition, we
estimate that they contain equal or more mildly deleterious nsSites, as
compared with immune system or random genes. Accordingly, a
wider spread of susceptibility alleles over larger-sized gene regions,
potentially combined with lower allele frequencies, could contribute
to a reduced yield of association studies.
Conclusions: One consequence could be a greater required effort for
imputing susceptibility alleles.
105

POSTER SESSION II
ABSTRACTS
106

ELSI, COUNSELING, AND GENETIC TESTING
PP76 DO PARTICIPANTS IN SEQUENCING STUDIES WISH
TO BE INFORMED OF THEIR RESULTS?
E. Bui, L. Kassem*, F. McMahon
Human Genetics Branch, Intramural Research Program, National
Institute of Mental Health/National Institutes of Health
*kasseml@mail.nih.gov
Introduction: As whole-genome sequencing technology rapidly
advances, the debate surrounding the reporting of individual results to
participants increases, introducing many ethical and logistical
issues. While these issues are being debated by bioethicists and
researchers, little is known about actual participants’ opinions.
Methodology: 59 volunteers were identified through an ongoing
bipolar disorder genetics study and surveyed using a questionnaire
we developed, the "Genome Sequencing Attitudes Survey
(GSAS).” Of study participants contacted, 70% agreed to participate
in the Genome Sequencing Attitudes Survey. The GSAS covers
three main areas: what information participants would like to receive
should their DNA be sequenced, what they would do with that
information, and any concerns about privacy they may have. All
interviews were conducted over the telephone by a single interviewer.
Results: The findings suggest a large majority of study volunteers
(97%) are interested in participating in sequencing studies. A large
proportion (86%) would like to be fully informed about their genetic
risks for various diseases, including those that are not actionable.
96% of respondents would consent to their anonymized personal data
being shared with other researchers. 41% of respondents also
expressed concerns about their insurance companies and other
entities accessing their personal genomic data, but would still be
interested in participating nonetheless.
Conclusions: Participants in genetics studies are very interested in
participating in detailed genome sequencing experiments and most
would appreciate or even expect to be offered individual results. The
public's knowledge about genetic risks, however, is quite lacking.
Researchers need to take these limitations into account when
providing individual results, and also should prepare to better educate
potential research participants about the implications of having this
information.
107
PP77 IDENTIFICATION OF CHROMOSOMAL
ALTERATIONS IN AUTISM SPECTRUM DISORDER’S
PATIENTS, TAMILNADU POPULATION, INDIA
M. Arun*, V. Balachandar, K. Sasikala
Human Molecular Genetics Laboratory, School of Life Sciences,
Bharathiar University
*arun47biotech@gmail.com
Introduction: Autism is a complex neurobiological disorder that
typically lasts throughout a person's lifetime. It is part of a group of
disorders known as autism spectrum disorders (ASD). It is often
associated with other conditions, such as disorders of the CNS
(tuberous sclerosis), developmental delay, attention deficit, epilepsy,
and anxiety and mood disorders. A reasonable extraction of the
overall data when applied to the male population finds 1 in 93 males
(54 per 10,000) are likely affected with autism. At the current time,
the exact causes of autism remain elusive, but researchers
increasingly believe that both genetics and environment play a role.
The prime aim of the present study was to identify the chromosomal
aberrations with autism patients in Coimbatore region.
Methodology: In order to investigate the possible cytogenetic
damage in autism patients, peripheral blood lymphocyte culture
(PBLC) method was carried out on the lymphocytes of 39 autism
patient samples and equal number of controls was selected, based on
the detailed questionnaire.An autism child has been followed up
regularly at frequent intervals of 4-6 weeks both by the paediatrician
and child psychologist. Parameters during follow up included enquiry
into the parents' assessment of the child as a whole, level of
hyperactivity after behavioural and pharmacological intervention.
Moreover, the present investigation has been conducted in the year of
2008 to 2011.In the present study volunteers provided blood samples
(5 ml) to establish cell cultures at 72 h. For karyotyping, 100
complete metaphase cells from each subject were evaluated using
Trypsin – Giemsa Banding method.
Results: In our study chromosomal alterations were frequently
observed in chromosomes 2, 3, 7, 16 and X (2q32, 3q25-q27, 7q31q35,
15q11-q13, 16p13, Xp22, and Xq13). The chromosomal
aberration frequency among 39 subjects was: 2/39 supernumerary
markers 7/39 deletions 1/39 duplication 1/39 inversions 2/39
translocations. In the present study, chromosomal aberrations showed
higher degree in experimentals compared to controls (P

PP78 BIOMARKERS IN PSYCHIATRY: FROM GENETICS
TO BIOLOGY TO PREDICTIVE MEDICINE
A. Niculescu*
Indiana University School of Medicine
*anicules@iupui.edu
Introduction: Biomarkers are at the interface of genetic research and
practical applications.
Methodology: Functional genomics has emerged as a useful partner
to classic genetic approaches, and combined approaches may provide
shortcuts to discovery of genes and overall understanding of the
neurobiology involved.
Results: I will present multi-modal data from our group showing
how panels of markers identified through Convergent Functional
Genomics have predictive ability in independent cohorts, the key
litmus test for any genetic or biomarker study. Specifically, I will
present data on trait genetic testing for bipolar disorder, and state
blood biomarker testing for mood, hallucinations, delusions and
anxiety.
Conclusions: Lastly, I will describe prototypes of how such testing
could be used to categorize disease risk in individuals and aid
personalized medicine approaches in psychiatry.
108
PP79 ETHNIC DISPARITIES IN THE PERCEPTION OF
ETHICAL RISKS FROM PSYCHIATRIC GENETIC STUDIES
E. Nwulia*(1), M. Hipolito(1), W. Lawson(1), J. Nurnberger Jr(2)
1. Howard University 2. Howard University 3. Howard University 4.
Indiana University
*enwulia@howard.edu
Introduction: Participation of ethnic minorities, particularly Blacks
in psychiatric genetic studies have been poor. Existing literature
from studies of convenient community samples suggest that mistrust
of biomedical researchers, based on the historical legacy of the
Tuskegee study (Schultz et al., 2003), fear of harm (Murphy et al.,
2009), wariness of ultimate uses of information, e.g. misapplication
of genetic data to explain racial differences in intelligence (Hernstein
and Murray 1994), mental illness stigma and associated
misperception of etiology of mental illness (Furr et al., 2002) are
some of the potential impediments to representation of Blacks in
research. However, it is unknown if these concerns persist among
participants in an actual psychiatric genetic study.
Methodology: Research participants in the Bipolar Genome Study
(BIGS) were examined on six items of concerns in the Questionnaire
on Genetic Risk (QGR). Responses from non-Hispanic Black
(N=188) and White participants (N=1065) formed the base for this
analysis. Polytomous multinomial models were specified for analysis
of the likert-response format of participants concerns. Adjusting for
demographic variables, the independent association of ethnicity to
each of the six perceived concern items were examined using
multivariate multinomial logistic regression.
Results: Concerns about unfavorable consequences of conducting
psychiatric genetic study were prevalent in the whole sample. Blacks
expressed stronger concerns for all consequences except for medical
insurance (P

EPIGENOMICS
PP80 DISRUPTION OF EARLY MATERNAL CARE IN
RHESUS MACAQUES RESULTS IN ALTERED EPIGENETIC
REGULATION OF THE OXYTOCIN RECEPTOR (OXTR)
GENE
M. Baker*(1), S. Lindell(1), Q. Yuan(2), Z. Zhou(2), S. Suomi(3),
C. Barr(1)
1. Section of Comparative Behavioral Genomics, NIH/NIAAA/LNG
2. Section of Human Neurogenetics, NIH/NIAAA, LNG 3.
Laboratory of Comparative Ethology, NIH/NICHD
*bakermb@mail.nih.gov
Introduction: Oxytocin is a neuropeptide that produces affiliative,
amnesic and anxiolytic affects. Given its roles in these processes,
regulation of this system may moderate risk for stress-related
disorders. We wanted to examine effects of disruption of early
maternal care in rhesus macaque infants on binding of an activating
histone (H3K4me3) and mRNA expression levels in adult brain.
Methodology: Brains (N=14) were archived from male macaques
(M. mulatta) that were raised by their mothers (MR) or in peer-only
groups (PR), an established model of early adversity. Hippocampal
samples were dissected for DNA and RNA isolation. Chromatin
Immunoprecipitation was performed with anti- H3K4me3 antibody,
and ChIP- and RNA-seq were performed on an Illumina GAII. Data
previously generated by microarray was used to verify RNA-seq
results.
Results: We observed H3K4me3 binding that spanned the first exon
of the OXTR gene (Chr2: 52,233,200 – 52,234,100), with peak
binding observed in a central 300 nucleotide region. Both overall
H3K4me3 binding and within-peak binding were decreased in PR
monkeys (P = 0.01 and P = 0.005). OXTR mRNA expression levels
were also decreased (P = 0.008).
Conclusions: Variation in maternal care as it relates to oxytocin
system functioning has been demonstrated in rodents. Our results
show that disrupted maternal care produces decreased binding of an
activating histone and lower OXTR mRNA expression levels in adult
macaque brain. Early environment-induced epigenetic regulation of
OXTR may increase vulnerability to stress-related disorders, either
alone or interactively with functional genetic variation. It could also
produce long lasting effects on social cognition and affiliative
behavior.
109
PP81 DNA HYPOMETHYLATION OF MB-COMT
PROMOTER IN THE DNA DERIVED FROM SALIVA IN
SCHIZOPHRENIA AND BIPOLAR DISORDER
S. Nohesara(1), M. Ghadiri(1), H. Ahmadkhaniha(1), S.
Mostafavi(2), S. Thiagalingam(2), H. Mostafavi Abdolmalek*(1,2)
1. Tehran University of Medical Sciences 2. Boston University
*hamostafavi@yahoo.com
Introduction: The molecular basis of pathogenesis remains
unrecognized in major mental diseases despite extensive genetic
studies. This failure in the discovery of etiology of psychiatric
diseases directed the attention of the scientific community to the
possible contributions of epigenetic modulations such as DNA
methylation and histone modifications, which play important roles in
the regulation of gene expression in response to environmental
factors. However, most epigenetic modifications are tissue specific
and the availability of brain tissue to identify epigenetic aberrations
in living condition is limited. The detection of epigenetic
abnormalities in other tissues that represent the brain epigenetic
marks is one of the critical steps to develop diagnostic and
therapeutic biomarkers for mental diseases. Formerly, we analyzed
115 human post-mortem brain samples from the frontal lobe and
reported an increased expression of membrane-bound catechol-Omethyltransferase
(MB-COMT) due to DNA hypo-methylation of the
gene promoter as a risk factor for schizophrenia (SCZ) and bipolar
disorder (BD). Here, hypothesizing that those factors that lead to the
brain MB-COMT promoter DNA hypo-methylation may also cause
concurrent epigenetic aberrations in peripheral tissues, we analyzed
MB-COMT promoter methylation in DNA derived from the saliva in
SCZ, BD and control subjects
Methodology: DNA was extracted from saliva using oragene DNA
kit. Bisulfate DNA sequencing and quantitative methylation specific
PCR was used to measure the degree of MB-COMT
promoter DNA methylation in SCZ, BD, non-affected family
members of patients and control subjects (each group 20 cases).
Results: We found that similar to the brain, MB-COMT promoter
DNA is hypo-methylated (~%50) in DNA derived from the saliva in
SCZ and BD compared to the controls ( p=0.02 and 0.037,
respectively). DNA Methylation of MB-COMT promoter in
unaffected family members of patients was not different compared to
the control subjects.
Conclusions: These studies suggest that DNA methylation analysis
of MB-COMT promoter in saliva can be used as an available
epigenetic bio-marker for disease state in SCZ and BD.

PP82 EPIGENETIC MODELING OF SEROTONIN
TRANSPORTER IN NURSES FROM HIGH/LOW STRESS
WORKING ENVIRONMENT
J. Alasaari(1,2), M. Lagus(1,2), M. Härmä(3), S. Puttonen(3),
T. Paunio*(1,2)
1. National Institute for Health and Welfare 2. Helsinki University
Central Hospital 3. 3. Finnish Institute of Occupational Health
*tiina.paunio@thl.fi
Introduction: Methylation of genomic DNA is part of an epigenetic
regulatory system that has been linked to a number of adaptive
processes such as stress regulation and learning. Methylation states
of the CpG dinucleotides are dynamic and semi stable by nature and
when this occurs within a gene promoter region, the result is
silencing of promoter activity, ultimately leading to silencing of the
gene itself. Methylation has been suggested to play a significant role
in the interplay between gene and environment. The serotonin
receptor gene (SLC6A4), a key regulator of serotonergic
neurotransmission, is of particular interest in the context of
stress.Changes in serotonergic neurotransmission are implicated in
disorders such as alcoholism, autism, migraine headaches and major
depression.
Methodology: A cohort of 99 Finnish female shift working nurses
was recruited from five hospitals and four towns belonging to an
ongoing Finnish Public Sector Study. Participants were selected from
wards that were placed among highest or lowest quartiles on job
strain based on Karasek's Job Content Questionnaire. The division
into high and low job strain groups was based on the average of all
the answers of a ward. The high job strain study group (N=31)
consisted of nurses who had self-evaluated their own job strain at
least as high as their ward on average in the highest quartile on job
strain. The low job strain study group (N=46) consisted of nurses
who had self-evaluated their own job strain at least as low as their
ward on average in the lowest quartile on job strain. Individual
experiences from work-related stress and depression were assessed
by the Maslach Burnout Inventory - General Survey (MBI-GS) and
Beck Depression Inventory (BDI). The inclusion criteria was age
between 30-58 years, mother tongue Finnish, BMI under 35, at least
3 years work experience in the same ward and absenteeism from
work of no longer than 6 months during the past 3 years. Nurses with
high alcohol consumption, frequent smoking, hormonal medication
and medication affecting cognitive functions were excluded. We
genotyped the high and low job strain study groups by bisulfate
sequencing of CpG sites of a 200bp region upstream of SLC6A4 and
calculated methylation percentages for each CpG residue using
Sequence Scanner v1.0. The differences in the two groups were
evaluated using two-tailed student's T-test.
Results: None of the individuals in the study cohort scored 3.5 or
higher (severe burnout) in the MBI-GS. The percentage of
individuals scoring between 1.5-3.49 (moderate burnout) were 42%
and 11% in the high and low work strain groups respectively. The
percentage of individuals having mild depression (scores between 10-
18) was 39% and 11% in the high and low job strain groups
respectively. Bisulfite sequencing of the promoter region of SLC6A4
revealed a robust and consistent difference between methylation
status of individuals from the two job strain groups at the five CpG
sites examined. The CpG methylation in the high work strain group
was lower as compared to the low work strain group at all five sites,
ranging from 6 to 13% in the low strain and from 3 to 9% in the high
strain group (P=0.001-0.02, respectively).
Conclusions: The results evidence for hypomethylation of promoter
region of serotonin transporter in adaptation to environmental stress.
Environmental stress may have lasting effects in the epigenome and
gene regulation.
110
PP83 COMPLEXITY ANALYSIS OF COMPLEX DISEASE:
SCHIZOPHRENIA
C. Smith*(1), K. Huang(2)
1. Boston Univeristy 2. Federal Institute of Technology
*clsmith@bu.edu
Introduction: Schizophrenia is a complex disease linked to both
genetic and environmental factors. Most recent research focuses on
identifying the genetic components of disease. Large international
genome wide studies identified rare and common alleles of over 100
genes linked to schizophrenia, as well an increased level of copy
number variants. Environmental components linked to disease occur
early during development and include malnutrition, folate deficiency,
viral infection, and elder fathers. Our focus has been on
understanding how genetic and environmental components
interaction.
Methodology: Here, we present the results of preliminary studies
using complexity modeling methods and the concept of emergence to
ask what influences the level of schizophrenia in a population.
Results: The results suggest that the level of schizophrenia in a
population is correlated with the de novo mutation rate.
Conclusions: These results demonstrate the usefulness of complexity
approaches for understanding how the multiple factors linked to
schizophrenia interactact. Future analysis will apply additional
principles of complexity analysis to further understand the
complexities of schizophrenia.

PP84 ALTERNATIVE STRATEGIES FOR CALCULATING
ANTIPSYCHOTIC DOSAGE EQUIVALENTS:
ASSOCIATION WITH DIFFERENT ETHNIC CLUSTERS
A. Hassan*, V. De Luca, A. Ravindran, C. Teo, J. Kennedy
University of Toronto
*nabeel.hassan@utoronto.ca
Introduction: BACKGROUND:Side effects of antipsychotic
medication are among the first reasons for noncompliant with
treatment for schizophrenia or schizoaffective disorder. It is very
common but hard to predict. These side effects are usually seen
above the recommended dosage of antipsychotic prescription, which
falls between 300 and 1000 chlorpromazine equivalents (CPZe) per
day. Several studies have indicated that demographic characteristics
can influence the individual’s dosage of medication to fall above the
recommended range. Some of the factors included to influence excess
antipsychotic dosing were the hospital cultures. A number of
guidelines have been developed to calculate the antipsychotic dosage
equivalents.
AIM: This retrospective study determines if high dosing of
antipsychotic is more common for certain ethnicity considering both
the self-reported ethnicity and the geographical ancestry calculated
using 191 DNA markers.
Methodology: We collected ethnicity data (self-reported) and DNA
sample from 241 schizophrenia patients at CAMH. We calculated the
CPZe at the time of the assessment as our main outcome.
Results: We did not find any significant difference between White
Europeans and Non White Europeans (self-reported) regarding the
CPZe (p=0.23) furthermore when we considered the geographical
ancestry determined by using the 191 SNPs we could not find any
association between the White ancestry and CPZe.
Conclusions: Our preliminary analysis shows that there is no
evidence that different ethnic groups receive different dose of
antipsychotics. However, there are many ways to calculate CPZ
equivalents doses and this makes it more difficult to perform
replication studies.
111
PP85 CEREBRAL DOMINANCE IS EPIGENETICALLY
TRANSMITTED
T. Crow(1), S. Leask*(2)
1. University of Oxford 2. University of Nottingham
*stuart.leask@nottingham.ac.uk
Introduction: Approximately 90% of individuals are right-handed, a
population characteristic that distinguishes humans from the great
apes. A single Mendelian gene with two alleles has been suggested. It
has been proposed that cerebral asymmetry is the defininig feature of
the human brain, and the location of the variation underlying
psychosis. Relative handskill is an index of cerebral asymmetry, and
has been found to correlate with verbal and non-verbal ability in the
general population.
Methodology: Here we investigate handedness at age 11 years as a
continuous variable in relation to parental age at the birth of the child.
If determined by DNA sequence (Mendelian) variation the age of a
parent would be without influence.
Results: On the contrary we find that mothers below the age of 20
are increasingly likely to have children who are more left-handed
than expected; fathers below the age of 20 have children who are
more right-handed. Thus variation in handedness is not Mendelian,
but a function of developmental stage and sex of the parent.
Conclusions: The analysis reveals an epigenetic trans-generational
influence relating to the faculty that defines the species – language.
Such transmission is relevant to human-specific heritability
predisposing to neuropsychiatric disease.
Crow, TJ, Crow, LR, Done, DJ, & Leask, S.J. 1998. Relative hand
skill predicts academic ability: global deficits at the point of
hemispheric indecision. Neuropsychologia 36(12): 1275-1282.
Peters, M, Reimers, S. & Manning, T.J. 2006. Hand preference for
writing and associations with selected demographic and behavioral
variables in 255,100 subjects: The BBC internet study. Brain &
Cognition 62: 177-189.

PHENOTYPES & ENDOPHENOTYPES
PP86 GENETIC PLASTICITY IN INDISCRIMINANT
BEHAVIOR AS A CONSEQUENCE OF EARLY SEVERE
SOCIAL DEPRIVATION AND INSTITUTIONAL CARE
S. Drury*(1), C. Nelson(2), N. Fox(3), C. Zeanah(1), K. Theall(1)
1. Tulane University 2. Harvard 3. University of Maryland
*sdrury@tulane.edu
Introduction: Recent theories challenge the vulnerability/resilience
concept of gene-environment interactions suggesting instead
that these interactions are better characterized in terms of biological
sensitivity to context. In this model genetic variation results in
greater sensitivity to the environment, for better or worse. To test this
model we explored the genetic contribution to indiscriminant social
behavior, an established lasting behavioral construct prevalent in
children exposed to early severe social deprivation. As symptoms of
indiscriminant behavior develop specifically in the environmental
setting of pathogenic caregiving and only a subset of children recover
when placed in an enhanced environment genetic plasticity may
explain this differential response to the caregiving environment.
Methodology: 98 children enrolled in the Bucharest Early
Intervention Project (BEIP) were randomized, before 30 months of
age, to either continued care as usual (CAUG) or high quality foster
care (FCG) and followed longitudinally. Indiscriminant behavior was
assessed at four time points by caregiver report using the same
validated semi-structured interview, the Disturbances of Attachment
Interview (DAI). (2)We examined the association of indiscriminant
behavior at each time point with functional polymorphisms in two
genes previously associated with differential susceptibility to early
adversity, Brain Derived Neurotrophic Factor (BDNF) val 66met and
the serotonin transporter (5HTT) 5httlpr. We additionally explored
the hypothesis that the met allele of BDNF and the short allele of the
5httlpr would reflect elevated sensitivity to change in the caregiving
environment such that they would be associated with the highest level
of symptoms in the CAUG but the lowest level of symptoms when
children were placed in foster care. Finally as these two
polymorphisms have previously been found to have an additive
influence on outcomes (3)we explored the association between
indiscriminant symptoms and a combined plasticity genotype (met
allele carriers and s/s homozygotes).
Results: An interaction between group status (FCG or CAUG) and
genotype was detected at multiple time points. Children with the s/s
5httlpr genotype or carriers of the met 66 allele in BDNF
demonstrated both the greatest decrease in DAI scores in the FCG
and the highest persistent rate of indiscriminate social behavior in the
CAUG. Regression analysis revealed that 5httlpr genotype had the
greatest impact on change in DAI score between baseline and 42
months(p=.02, r2=.17) while the greatest impact of BDNF genotype
occurred between 30 and 54 months (p=003 r2=.11). Children with
both s/s 5htt genotype and met/ allele carriers of BDNF in the CAUG
had the highest number of indiscriminate symptoms at 54 months
while those with the same genotype in the FCG had the lowest
number of symptoms at 54 months.
Conclusions: These findings represent the first known genetic
associations with indiscriminant social behavior. This is the first
study, to our knowledge, to demonstrate genetic biological sensitivity
to context in the same children exposed to well-defined changes in
the caregiving environment associated with institutional rearing.
These findings add to the growing literature demonstrating biological
sensitivity to context and highlight the need for careful consideration
of this model in future gene-environment interaction studies.
112
PP87 PATTERNS OF DEFICITS IN BRAIN FUNCTION IN
BIPOLAR DISORDER AND SCHIZOPHRENIA: A CLUSTER
ANALYTIC STUDY
M. Hall*(1,2,3), J. Smoller(3), K. Schulze(4), F. Rijsdijk(4), P.
Lee(3), G. Taylor(2), E. Bramon(4), M. Coleman(1), R. Murray(4),
D. Salisbury(2), D. Levy(1)
1. Psychology Research Laboratory, McLean Hospital, Harvard
Medical School 2. Cognitive Neuroscience Laboratory, McLean
Hospital, Harvard Medical School 3. Psychiatric Genetics Program in
Mood and Anxiety Disorders, Massachusetts General Hospital,
Harvard Medical School 4. Division of Psychological Medicine,
Institute of Psychiatry, King's College London
*mhall@mclean.harvard.edu
Introduction: Historically, bipolar disorder (BPD) and schizophrenia
(SCZ) have been considered distinct disorders with differing
etiologies and courses of illness. Growing evidence suggests that
overlapping genetic influences contribute to risk for these disorders
and that each disease is genetically heterogeneous. In this study, we
explored the use of cluster analytical approach to extract
neurophysiological profiles in patients with diagnoses of SCZ or
BPD, their unaffected relatives, and control subjects. The main goals
of this study were to: 1) identify and characterize distinct
neurophysiological functional profiles in independent samples of
psychotic patients, their unaffected first-degree relatives and controls
2) assess the magnitude and type of brain functional abnormalities in
relation to DSM diagnoses and 3) compare these empirically derived
clusters of psychotic patients on demographic features and illness
characteristics.
Methodology: Seven auditory neurophysiologic phenotypes,
including P50 sensory gating, evoked gamma band response, P3
amplitude, P3 latency, P2 amplitude, N1 amplitude, and MMN
amplitude, were collected from two independent cohorts of SCZ and
BPD families at two research institutions, including probands
(n=157), relatives (n=82) and well controls (n=230). The individuals
were clustered using the K-means algorithm.
Results: Three neurophysiologically distinct profiles emerged from
the cluster analysis (Figure 1). Individuals in cluster one, the global
impaired group, exhibited severe functional abnormalities and had
the worst scores on all measures. Individuals in cluster two, the high
sensory processing group, performed the best on tasks that tap the
early stages of sensory processing. Individuals in cluster three, the
high cognitive group, had the best scores on tasks that probe
inhibitory function and higher cognitive processes. These overall
patterns were observed in both independent samples and thus seem to
robustly reflect three distinct neurocognitive profiles. Significant
heritability was found for these three empirically derived behavioral
profiles. Notably, these profiles are not specific to either SCZ or
BPD.
Conclusions: The results suggest that three distinct clusters of
individuals can be identified who may differ in underlying
neurobiology and genetic risk factors. These results raise the
intriguing possibility that neurocognitive profiles may be more
powerful discriminators than diagnoses in genetic analyses.

PP88 ROLE OF THE GRIN2B GENE IN THE PRESENCE OF
COMORBID PSYCHIATRIC DIAGNOSES IN WOMEN WITH
BULIMIA NERVOSA
Z. Yilmaz*(1,2), A. Kaplan(1,2), C. Zai(1,2), R. Levitan(1,2), J.
Kennedy(1,2)
1. University of Toronto 2. Centre for Addiction and Mental Health
*zeynep.yilmaz@utoronto.ca
Introduction: GRIN2B gene regulates the activity of NMDA
receptor NR2 subunit, which acts as the agonist binding site for
glutamate and has been associated with anxiety and impulse controlrelated
disorders. Majority of patients with bulimia nervosa (BN) also
report a history of anxiety disorders and a significant proportion have
impulse control problems, suggesting that BN may also be associated
with glutamatergic abnormalities. The purpose of this study is to (1)
examine the frequency of GRIN2B genetic variants in BN and
healthy controls and (2) explore the role of the GRIN2B gene in
comorbid psychiatric disorders among bulimic women.
Methodology: For the first part of the study, we genotyped 243
women with BN and equal number of ethnicity-matched female
controls for GRIN2B rs2284411, rs1806201, rs1019385 and rs890,
markers previously associated with psychiatric disorders. We then
performed genetic analyses on the BN probands to investigate if the
GRIN2B variants and haplotypes were associated with comorbid
psychiatric diagnoses and severity of eating disorder symptoms.
Results: The data analysis for the first part of the study is currently
underway. Within the BN group, we found a significant association
of GRIN2B markers and haplotypes with a lifetime history of anxiety
disorders (p = .015). GRIN2B genotypes or haplotypes were not
associated with childhood ADHD or history of substance use in BN
probands.
Conclusions: To our knowledge, this is the first study to look at the
role of GRIN2B gene in BN. The pathophysiology of BN with
comorbid anxiety disorders may be a distinct subphenotype related to
underlying glutamatergic abnormalities, and these finding may have
implications for treatment for BN patients with comorbid anxiety
disorders.
113
PP89 INVESTIGATION OF THE ASSOCIATION OF
POLYGENIC SIGNALS FOR ADHD TO PREDICT
COGNITIVE MEASURES THAT SHARE GENETIC
INFLUENCES WITH ADHD
G. Mould*(1), T. Price(1), T. Banaschewski(4), M. Gill(2), I.
Manor(5), A. Miranda(6), F. Mulas(7), R. Oades(8), A.
Rothenberger(3), H. Royers(12), H. Steinhausen(9,10,11), J. van der
Meere(13), S. Faraone(14), P. Asherson(1), J. Kuntsi(1)
1. King's College London 2. Trinity Centre for Health Sciences 3.
University of Göttingen 4. University of Heidelberg 5. S. Herzog
Memorial Hospital 6. University of Valencia 7. La Fe University
Hospital 8. University of Duisburg-Essen 9. University of Zurich 10.
University of Basel 11. University Hospital Aarhus 12. Ghent
University 13. University of Groningen 14. State University of New
York Upstate Medical University
*glenn.mould@kcl.ac.uk
Introduction: ADHD is associated with multiple cognitive
performance deficits. Among these Kuntsi et al (2010, Archives of
General Psychiatry) selected the most promising indicators for a
multivariate familial factor analysis. Two familial cognitive
impairment factors were identified, which accounted for 85% and
13% of the familial variance on ADHD. The first, large factor
captured speed and variability of reaction times (RT) and the second
factor captured commission (Ce) and omission (Oe) errors on a
go/no-go task. Using the same sample we now evaluate whether
polygenic signals for ADHD generated from genome wide SNP data
are associated with the most promising cognitive variables.
Methodology: Analysis used data from a collaboration of 8 teams
from the International Multi-Centre ADHD Gene (IMAGE) project.
Probands were all combined type ADHD, of white European decent
and aged 6-18. DNA was available from probands and both parents.
The transmission disequilibrium test (TDT) was conducted and the
data used to generate polygenic scores at different significance
thresholds. Polygenic scores from 352 parent-proband trios were used
to predict cognitive performance using regression analysis, with RT
variability, Oe, Ce and IQ using a 4-fold cross validation procedure.
SNPs included in the analysis were in linkage equilibrium, to
minimise the use of redundant genetic variation and potentially
enhance statistical power.
Results: Analyses tested ADHD associated genotype scores at
different p-value thresholds. Significant associations were detected
for Oe and RT variability at thresholds of P

PP90 THE INFLUENCE OF SCHIZOPHRENIA-RELATED
DISC1 POLYMORPHISMS ON SENSORIMOTOR GATING,
COGNITION AND PERSONALITY IN HEALTHY MALES
P. Bitsios*(1), P. Roussos(1,2), S. Giakoumaki(1)
1. Department of Psychiatry and behavioral Sciences, University of
Crete 2. Department of Psychiatry, Mount Sinai School of Medicine
*pbitsios@med.uoc.gr
Introduction: There is evidence supporting a role for the DISC1
locus in schizophrenia, however the impact of DISC1 risk
polymorphisms on schizophrenia endophenotypes has not been
studied extensively.
Methodology: We selected DISC1 polymorphisms that are
functional or have shown significant association with SZ or SZrelated
endophenotypes (rs3738401, rs1538979, rs2492367,
rs6675281, rs1984895, rs1000731, rs999710, rs821577, rs821616,
rs821633, rs3737597). These polymorphisms were analyzed in 530
healthy males, phenotyped for acoustic startle and prepulse inhibition
(PPI), performance in verbal and working memory, executive
function, schizotypy, trait anxiety and affective personality traits.
QTPHASE from the UNPHASED package was used for the
association analysis of allelic data, withp values corrected for
multiple testing by running 10000 permutations of the data.
Results: The rs999710 T allele was most strongly associated with
reduced PPI (p

the worse mean scores when compared to mixed episode and
depression. In manic patients rs4680 allele G+ showed better
performance in an executive function test. Cognitive performance
was better for manic episode patients with G at rs165599 as shown
through executive function tests: SCWT-1 SCWT-2 and SCWT-2
errors. Mixed episode rs4680 G+ patients performed better in verbal
fluency, non-verbal memory and executive function tests. Mixed
episode patients with rs165599 G displayed higher mean scores in
intelligence and executive function. Depressive patients were not
significantly different from controls in all tests.
Conclusions: Our data shows that rs4680 and rs165599 G+
individuals had better cognitive function than G- during manic and
mixed episodes. During manic episodes G+ had better performance
than G- on executive function tests, and those with mixed episodes
G+ patients performed better in executive, memory, verbal fluency
and intelligence tests. We hypothesize that COMT genotype may
partly determine the cognitive disorganization in some patients
during mania and mixed episodes.
115
PP92 PCLO GENOTYPE EFFECT ON NEURAL
CORRELATES OF EMOTIONAL MEMORY AND THE
INFLUENCE ON THE HPA AXIS
S. Woudstra*(1,2,3,7), W. Hoogendijk(1,7), Z. Bochdanovits(2,8),
M. van Tol(1,3,4,6), L. Demenescu(5), S. Vreeburg(1), N. van der
Wee(3,4), F. Zitman(3), E. Opmeer(6), A. Aleman(6), B.
Penninx(1,2,3), D. Veltman(1)
1. Department of Psychiatry, VU university Medical Centre 2.
Department of Medical Genomics, VU university Medical Centre 3.
Department of Psychiatry, Leiden University Medical Centre 4.
Leiden Institute for Brain and Cognition, Leiden University 5.
Department of Psychiatry and Psychotherapy, RWTH Aachen
University 6. BCN Neuroimaging Center, University Medical Center
Groningen 7. Neuroscience Campus Amsterdam 8. TI Pharma
*s.woudstra@vumc.nl
Introduction: Emotional memory information processing is thought
to be related to anhedonia, one of the core symptoms in major
depressive disorder (MDD). It was found that glucocorticoids -
released by the hypothalamic-pituitary-adrenal (HPA) axis -
influence emotional memory information processing and may
contribute to the neuroendocrine abnormalities found in MDD
(Wingenfeld & Wolf, 2011). Emotional memory information
processing is also thought to be associated with monoamines (Merens
et al., 2007). A GWA study for MDD implicated piccolo (PCLO),
which protein is involved in monoaminergic neurotransmission
(Sullivan et al., 2009), and we hypothesize that the piccolo risk allele
(PLCO+) is associated with altered brain activity during an emotional
word memory task. In addition, we hypothesize that the PCLO
genotype moderates the association between emotional memory
information processing and the HPA axis. Therefore, we will
investigate whether PCLO+ is associated with dysregulation of the
HPA-axis.
Methodology: Using both genotype and functional MRI data from
118 subjects (average age 38.4 yrs 62% female) from the NESDA
neuroimaging study, we conducted an ANOVA with genotype as
independent factor (p

PP93 A MULTI-TIERED TRANSLATIONAL FRAMEWORK
FOR LONGITUDINAL PSYCHOSIS RESEARCH: THE
PSYCHOSIS CENTER LOWER SAXONY IN GÖTTINGEN,
GERMANY
M. Budde*(1), D. Reich-Erkelenz(1), H. Bickeböller(2), J.
Brockmöller(3), M. Tzvetkov(3), O. Gruber(1), P. Falkai(1), T.
Schulze(1)
1. Georg-August-University, University Medical Center, Department
of Psychiatry and Psychotherapy 2. Georg-August-University,
University Medical Center, Department of Genetic Epidemiology 3.
Georg-August-University, University Medical Center, Department of
Clinical Pharmacology
*monika.budde@med.uni-goettingen.de
For a clinician, the longitudinal course of a patient suffering from
schizophrenia (SZ) or bipolar disorder (BD) is an important
phenotypic feature that is used to guide treatment options and
prognostic considerations. Moreover, it is the course (e.g. cognitive
functioning, social withdrawal) that determines the economic burden
of psychosis, both for the individual patient and society.
Despite this, hardly any systematic analyses of complex genotypephenotype
relationships in the longitudinal course of SZ and BD can
be found. Therefore the Psychosis Center Lower Saxony has been
established in Göttingen, Germany, aiming at analyses based on a
large sample comprising 3000 prospectively-followed patients and
prospectively-followed 3000 controls. To allow for the recruitment of
sufficiently large cohorts and their continued longitudinal follow-up,
the Psychosis Center is tightly integrated with the inpatient and
outpatient sections of the Department of Psychiatry and
Psychotherapy of the University Medical Center of the Georg-
August-University and will have associated recruitment centers at 13
collaborating hospitals in Lower Saxony, Northern Hesse and
Bremen.
Each patient of 18 years of age or older with a DSM-IV diagnosis of
SZ or BD can take part in the project. Over a period of at least 1.5
years each patient and control will be seen in regular visits every 6
months or earlier, if needed (e.g. in case of relapse). At each visit,
phenotypic features like differentiated psychopathology, response to
treatment including adverse events, global functioning,
neuropsychological performance, and life events will be assessed.
These assessments will we paralleled with structural and functional
imaging.
In the long run, the major aim of the Psychosis Center Lower Saxony
is on the one hand the creation of a phenotypic database that can
easily be linked to already existing phenotypic databases and on the
other hand the creation of a biobank (PsyCourse Biobank Göttingen)
for genomics, epigenomics, transcriptomics, and proteomics.
116
PP94 WHITE MATTER ABNORMALITIES IN PSYCHOSIS
ARE RELATED TO INCREASED GENETIC RISK
E. Sprooten*, A. McIntosh, S. Lawrie, J. Sussmann
University of Edinburgh
*andrew.mcintosh@ed.ac.uk
Introduction: Several lines of clinical, epidemiological and
molecular evidence suggest that abnormalities of white matter may
convey risk to major psychiatric disorder. Using diffusion tensor
imaging (DTI), we sought to address whether white matter
abnormalities are present in 1) individuals at high familial risk and 2)
carriers of specific risk variants in NRG1-ErbB4 or DISC1
Methodology: We used DTI in two large samples of people at highrisk
of either schizophrenia or bipolar disorder to assess the
relationship of fractional anisotropy to familial disease risk.
Secondly, using similar methods, we assessed whether reduced
fractional anisotropy was associated with functional risk variants in
NRG1 (rs6994992, type IV promoter variant), ErbB4 (rs4673628,
splice site) and DISC1 (rs821616, mis-sense)
Results: Reduced white matter integrity was found in subjects at high
risk of schizophrenia and in subjects at high risk of bipolar disorder
for genetic reasons. Reduced anisotropy was also found in individuals
with previously identified functional risk variants in the NRG1-
ErbB4 signalling pathway and in DISC1.
Conclusions: Emerging evidence from DTI suggests that risk
variants for major mental illness have effects on white matter
integrity that fail to respect diagnostic boundaries. This suggests that
white matter integrity may be a useful quantitative trait for the
identification of novel risk variants an that understanding its cellular
basis may yield information about the aetiology of major mental
illness.

PP95 THE GENETICS OF LANGUAGE LATERALIZATION
AND LEFT-HANDEDNESS: LINKAGE ANALYSIS IN A
DUTCH POPULATION ISOLATE
M. Somers*(1), R. Ophoff(2,4), R. Cantor(3), M. Aukes(1,5), K. van
Eijk(4), M. Dauwan(1), R. van 't Slot(4), E. Janson(4), M. Boks(1,5),
R. Kahn(1), I. Sommer(1)
1. Rudolf Magnus Institute of Neuroscience, Department of
Psychiatry, University Medical Center Utrecht 2. Center for
Neurobehavioral Genetics, Semel Institute for Neuroscience and
Human Behavior, UCLA 3. ) Department of Human Genetics, David
Geffen School of Medicine, UCLA 4. Department of Medical
Genetics, University Medical Center Utrecht 5. Julius Center for
Health Sciences and Primary Care, University Medical Center
Utrecht
*m.somers@umcutrecht.nl
Introduction: Investigating endophenotypes can be an additional
strategy to identify the genetic underpinnings of schizophrenia.
Extensive evidence shows that decreased language lateralization is a
useful endophenotype. Language lateralization is related to handpreference
as almost 100% of right-handers have left-hemispheric
lateralization, while left-handers show larger variability with 30%
having right-hemispheric or bilateral language lateralization. As such,
decreased language lateralization can be efficiently studied in nonschizophrenic
left-handed subjects. This study applied an
endophenotype approach to find genetic regions involved in
schizophrenia through linkage analysis of decreased language
lateralization and hand-preference, measured in large families with
multiple left-handers from a unique Dutch population isolate: the
former isle of Urk.
Methodology: DNA was collected from 369 subjects of 37 large
multi-generational families. Hand-preference was measured with the
Edinburgh Handedness Inventory (EHI) and language lateralization
was measured with functional transcranial Doppler (fTCD).
Genotyping with the Illumina HumanLinkage-24 panel (5913 SNPs)
was successful in 361 subjects. After quality control and
checking for mendelian inconsistencies using PLINK and MERLIN,
155 SNPs and 6 subjects were excluded, leaving a total of 355
subjects with 5420 autosomal SNPs for linkage analysis with
MERLIN. A parametric rare-dominant single-gene fluctuating
asymmetry model (McManus 1985, van Agtmael et al, 2001) was
tested for hand-preference as dichotomous trait. Non-parametric
models were tested for hand-preference and language lateralization,
both as dichotomous and quantitative traits.
Results: The parametric analysis showed suggestive linkage in the
22q13 region (HLOD Max=2.24) for hand-preference. Non-parametric
multipoint analysis showed overlapping suggestive linkage in the
same region (LODMax=2.69). There was no linkage for handpreference
as a quantitative trait. Non-parametric multipoint analysis
showed suggestive linkage for language lateralization as a
dichotomous trait in the 7q34 region (LODMax=2.65) and as a
quantitative trait in the 6p22 region (LODMax=2.56).
Conclusions: Our results indicate that left-handedness, non-left
hemispheric language lateralization and degree of language
lateralization show genetic linkage in this population isolate, which is
consistent with the notion that these traits have a genetic basis. The
absence of overlap between the linked regions can point towards at
least partly separate genetic underpinnings for each trait. Findings
from our parametric analysis are consistent with a major gene model
for hand-preference. The markers in the three regions will be tested
for association with the traits the regions are linked to, in order to
further investigate the validity of the current findings.
117
PP96 THE KCNH2 GENE IS ASSOCIATED WITH
NEUROCOGNITION AND THE RISK OF SCHIZOPHRENIA
K. Ohi*(1,3), R. Hashimoto(1,2,3), Y. Yasuda(1,3), M.
Fukumoto(1,3), H. Yamamori(1,3,4), K. Kamino(1,5), T.
Morihara(1), M. Iwase(1), H. Kazui(1), M. Takeda(1,2)
1. Department of Psychiatry, Osaka University Graduate School of
Medicine 2. Molecular Research Center for Children's Mental
Development, United Graduate School of Child Development, Osaka
University, Kanazawa University and Hamamatsu University School
of Medicine 3. CREST (Core Research for Evolutionary Science and
Technology of JST (Japan Science and Technology Agency) 4.
Department of Molecular Neuropsychiatry, Osaka University
Graduate School of Medicine 5. Shoraiso National Hospital
*ohi@psy.med.osaka-u.ac.jp
Introduction: A genetic variant (rs3800779 M30) in the KCNH2
gene has been associated with schizophrenia, a lower intelligence
quotient (IQ) and processing speed scores, altered brain functions and
increased KCNH3-3.1 mRNA levels in the hippocampus. The aims of
this study were to investigate whether the KCNH2 polymorphismis
associated with schizophrenia-related neurocognitive deficits
andtoconfirm the association between the variant and schizophrenia.
Methodology: The effects of the riskgenotype on IQ and seven
neurocognitive batteries were examined by the analysis of covariance
in 191 healthy subjects. We performed a meta-analysis of the
association between M30 and schizophrenia using five independent
ethnic groups (1,720 cases 2,418 controls).
Results: Consistent with the previous study, we provided evidence
that subjects with the risk T carriers had significantly lower IQ scores
than those with the G/G genotype(p=0.048, Figure1A). Of the seven
neurocognitive batteries, subjects with the risk genotype
demonstrated lower performances on attention/vigilance (p=0.0079,
Figure1B) and working memory (p=0.0066, Figure1C) relative to
subjects with the G/G genotype. Meta-analysis demonstrated
evidence for an association between M30 and schizophrenia without
showing heterogeneity across studies (odds ratio=1.18, p=0.0017).
Conclusions: These data suggest that the KCNH2 polymorphism
could be associated with schizophrenia-related neuropsychological
deficits and the risk of developing schizophrenia.

PP97 VARIANTS OF THE RELA GENE ARE ASSOCIATED
WITH SCHIZOPHRENIA AND THEIR STARTLE
RESPONSES
R. Hashimoto(1,2,4,7), K. Ohi(2,4), Y. Yasuda(2,4), M.
Fukumoto(2,4), H. Yamamori(2,3,4), H. Takahashi(2,4), M.
Iwase(2), T. Okochi(4,5), H. Kazui(2), O. Saitoh(6), M. Tatsumi(8),
N. Iwata(4,5), N. Ozaki(4,9), K. Kamijima(10), H. Kunugi(7), M.
Takeda(1)
1. Molecular Research Center for Children's Mental Development,
United Graduate School of Child Development, Osaka University,
Kanazawa University and Hamamatsu University School of Medicine
2. Department of Psychiatry, Osaka University Graduate School of
Medicine 3. Department of Molecular Neuropsychiatry, Osaka
University Graduate School of Medicine 4. CREST (Core Research
for Evolutionary Science and Technology), JST (Japan Science and
Technology Agency) 5. Department of Psychiatry, Fujita Health
University School of Medicine 6. Department of Psychiatry, National
Center Hospital 7. Department of Mental Disorder Research,
National Institute of Neuroscience, National Center of Neurology and
Psychiatry 8. Yokohama Shinryo Clinic 9. Department of Psychiatry,
Nagoya University Graduate School of Medicine 10. Department of
Psychiatry, Showa University School of Medicine
Introduction: The pathogenesis of schizophrenia is thought to
involve aberrant immune and inflammatory responses. Nuclear factor
kappa B (NF-kappaB) plays important roles in the immune and
inflammatory responses. The v-rel avian reticuloendotheliosis viral
oncogene homolog A (RELA) gene encodes the major component of
the NF-kappaB complex.
Methodology: We genotyped four single nucleotide polymorphisms
(SNPs) in the RELA gene and performed a gene-based association
analysisusing 1,224 patients with schizophrenia and 1,663 controls.
In silico genotype-gene expression analysis was performed using web
database and the WGAViewer software. The impact of four RELA
polymorphisms on prepulse inhibition (PPI) was investigated in 53
patients with schizophrenia.
Results: We found significant associations of three SNPs [rs7119750
(SNP1): p=0.0080, rs2306365 (SNP3): p=0.0031 and rs11820062
(SNP4): p=0.00011] with schizophrenia and stronger evidence for
association in a multi-marker sliding window haplotype analysis (the
lowest p=0.00006). The association between this gene and
schizophrenia was evident in male subjects but not in female
subjects, when separately analyzed by gender. In silico
analysis revealed that these three schizophrenia-associated SNPs
might be related to RELA mRNA expression in immortalized Blymphocytes.
In silico analysis also suggested the putative promoter
SNP4 might disrupts the consensus transcription factor binding
sequence of the androgen receptor. In addition, we provided evidence
that at risk genotypes of three SNPs (SNP1, 3 and 4) were associated
with deficits in PPI, however, there was no effect of the one non-risk
SNP2 on PPI (Figure1).
Conclusions: These findings suggest that variants of the RELA gene
are associated with risk for schizophrenia and PPI deficits in a
Japanese population.
118
PP98 GENETIC DETERMINANTS OF IMPAIRED BRAIN
FUNCTION IN SCHIZOPHRENIA
S. Bergen(1,2,3), S. Purcell(1,2,3), J. Goldstein(1,4), R.
McCarley(1,5), L. Seidman(1,6), M. Shenton(1,4,5), T. Woo(1,7), T.
Petryshen*(1,2,3)
1. Dept of Psychiatry, Harvard Medical School 2. Psychiatric and
Neurodevelopmental Genetics Unit, Center for Human Genetic
Research, Massachusetts General Hospital 3. Stanley Center for
Psychiatric Research, Broad Institute 4. Dept of Psychiatry, Brigham
and Women's Hospital 5. Dept of Psychiatry, VA Boston Healthcare
System 6. Dept of Psychiatry, Beth Israel Deaconess Medical Center
7. McLean Hospital
*petryshen@chgr.mgh.harvard.edu
Introduction: Schizophrenia (SCZ) is characterized by severe
impairments in cognition and brain function for which the underlying
neural abnormalities are essentially unknown. Recently, the SCZ
genetics field has been ignited by the identification of genetic
variants contributing to SCZ susceptibility from the consensus of
large-scale genome-wide association studies (GWAS). The next
logical and necessary step is to translate these findings into a better
understanding of cognitive and brain function impairments in SCZ to
elucidate the molecular mechanisms of neural circuit dysfunction in
this disease.
Methodology: The genetic contribution to impaired brain function in
SCZ is being evaluated using a unique case/control sample (total N =
347) spanning prodrome, first episode, and chronic SCZ stages with
longitudinal data from clinical, cognitive, structural and functional
imaging, electrophysiological, and hormonal phenotypic
domains. Candidate genes are selected that have a priori evidence
for involvement in SCZ or brain function from genome-wide
association studies (GWAS) or cell-specific postmortem expression
studies. Regression analysis is performed using PLINK for each
phenotypic measure, as well as multivariate analysis of principle
components across phenotypic domains. Empirical P values are
calculated by point-wise permutation for each SNP test.
Results: Preliminary regression analysis was performed using a
subset of 115 subjects (51 control, 64 SCZ across prodrome, first
episode, and chronic stages) and 6 cognitive measures assessing
attention/processing speed, language function, visuospatial ability,
verbal learning & memory, and working memory. 61 SNPs tested
were located in 23 genes/loci with near or above genome-wide
significance in published GWAS of SCZ or cognition, or in the
Psychiatric GWAS Consortium SCZ mega-analysis, or with
significantly different expression in SZ cortical neurons. In combined
analysis of cases and controls, the SCZ risk gene neurogranin
(NRGN) was associated with language function and verbal learning
(rs548181; WASI vocabulary, P = 0.003; WMS-3 logical memory, P
= 0.007), in support of mouse studies reporting a role for NRGN in
cognition. The KIBRA gene, originally identified in a memory
GWAS, was associated with attention/processing speed (rs17070145;
Trial-making Part A, P = 0.01) in this sample. Expanded analysis of
additional subjects and other phenotypes (gray matter MRI and white
matter DTI measures, ERP components, hormone levels, working
memory brain activity) is ongoing.
Conclusions: This deeply-phenotyped patient sample provides an
exceptional opportunity to elucidate the functions of existing SCZ
risk variants in regulating specific neural processes underlying
pathophysiology. Initial analyses indicate associations between
cognitive traits and the NRGN and KIBRA genes which provide
insights into their disease-relevant functions. Analysis of other
phenotypes within and across neuroanatomical, functional, and
physiological domains may highlight genetic relationships suggesting
common neural mechanisms underlying brain function deficits in
SCZ.

PP99 BDNF VAL66MET INTERACTS WITH STRESS AT
AGE 13 TO PREDICT DEPRESSION AT AGE 15
R. Salk*, L. Abramson, J. Hyde
University of Wisconsin-Madison
*rsalk@wisc.edu
Introduction: The brain derived neurotrophic factor (BDNF) gene is
an identified and theoretically relevant gene for investigating geneenvironment
interactions across development that predict depression
(Casey et al., 2009). The BDNF gene codes for a neurotrophin that is
highly expressed in the central nervous system, heavily involved in
synaptic plasticity, and strongly influenced by stress. This study
explored BDNF-stress interactions across development to predict
depression symptoms in adolescence.
Methodology: Participants were 228 Caucasian youth (50% female)
who have participated in a longitudinal study of child development
since birth (the Wisconsin Study of Families and Work, Hyde et al.,
1995). Data were collected during the summers following Grades 5
(mean age = 11.49, SD = .29, 2002 and 2003), 7 (M = 13.49, SD =
.31, 2004 and 2005), and 9 (M = 15.48, SD = .31, 2006 and 2007). At
all time-points participants completed a measure of depression
symptoms (CDI), negative life events (APES), and peer sexual
harassment victimization (PSHV AAUW items). DNA was collected
with buccal swabs at age 15. The recessive homozygous group was
combined with the heterozygotes: Met carriers (both Val/ Met and
Met/Met n = 60) and Val/Val homozygotes (n = 168).
Results: Multiple regression was used to test whether the BDNF
Val66Met polymorphism would interact with negative life events or
peer sexual harassment victimization to predict depression symptoms
at age 15 (controlling for depression symptoms at age 11). Maximum
likelihood parameter estimates with standard errors were used to
account for the skewed CDI scores. Sex and age 11 CDI were
included in the model to increase power to test substantive questions
about BDNF, stress measures, and their interaction on depression.
We first regressed age 15 CDI on gender, age 11 CDI, BDNF, age 13
APES, and the BDNF-APES interaction. The overall model
accounted for a significant amount of variance in depression, R 2 =
0.24, F(5, 222) = 3.72, p < .001. A significant main effect of BDNF
was observed, b = 3.58, t(222) = 2.47, p = .013, such that Met carriers
had more depressive symptoms than Val/Val individuals. A
significant main effect of age 13 stress was observed, b = 0.38, t(222)
= 3.24, p = .001, such that depression symptoms at age 15 increased
with increasing stress at age 13. BDNF moderated the stress effect on
depression, b = -0.41, t(222) = -2.54, p = 0.01. For Val/Val
individuals, more stress predicted increased depression, b = 0.38, t
(222) = 3.24, p = 0.001. Stress did not predict depression for Met
carriers, b= 0.02, t (222) = 0.14, p = 0.89. This genetic-vulnerability
by stress model was then repeated using age 13-peer sexual
harassment victimization as the stressor. A significant effect of the
BDNF-PSHV interaction was also observed, b = -0.58, t (222) = -
2.23, p = 0.026, with increasing levels of PSHV only increasing
depression symptoms in Val/Val individuals (b = 0.50, t(222) = 2.42,
p = 0.02).
Conclusions: Using both a general and specific measure of stress, the
current study demonstrates a genetic vulnerability-stress interaction
that predicts depression symptoms across development. BDNF
Val66Met significantly moderated the relationship between stress at
age 13 and depression symptoms at age 15 (averaging across gender
and controlling for depression symptoms at age 11). With increasing
stress at age 13, Val/Val youth were at increased risk for depression
symptoms at age 15 however, there was no association between age
13 stressors and age 15 depression for Met-carriers. Interestingly,
Met carriers had elevated depression symptoms regardless of stress,
whereas Val/Val individuals were stress reactive. Consistent with the
neurotrophic hypothesis of depression, the Met allele was the risky
allele for depressive symptoms under low to medium levels of stress
(likely because of its lower BDNF secretion and decreased synaptic
plasticity). However, under higher levels of stress, Val/Val
individuals were at increased risk for depression symptoms. These
findings support a nuanced depiction of BDNF Val66Met by stress
interactions that predict depression symptoms in adolescence.
119
PP100
WITHDRAWN

PP101 SCN1A ALTERS BRAIN STRUCTURE AND
MODULATES AGE-DEPENDENT ALTERATIONS IN
POSTERIOR CINGULATE ACTIVATION DURING A
WORKING MEMORY TASK
S. Meier*(1), T. Demirakca(2), W. Brusniak(3), I. Wolf(2), K.
Liebsch(3), N. Tunc-Skarka(2), V. Nieratschker(1), S. Witt(1), F.
Matthäus(4), G. Ende(2), H. Flor(3), M. Rietschel(1), C. Diener(3),
T. Schulze(5)
1. Department of Genetic Epidemiology in Psychiatry, Central
Institute of Mental Health, University of Heidelberg 2. Department of
Neuroimaging, Central Institute of Mental Health, University of 3.
Department of Cognitive and Clinical Neuroscience, Central Institute
of Mental 4. Institute of Applied Mathematics, University of
Heidelberg 5. Department of Psychiatry and Psychotherapy,
University Medical Center
*sandra.meier@zi-mannheim.de
Introduction: SCN1A encodesthe sodium channel alpha subunit and
is a susceptibility gene for neurological disorders. The C allele of the
SCN1A variant rs10930201 has recently been found associated with
poor short-term memory performance in a genome wide association
study. Further rs10930201 was observed to be related to brain
activity during a working memory task.
Methodology: As age strongly affects cognitive functioning and agerelated
changes in brain structure as well as in task-induced brain
activity are well documented, we investigated the effects of age
andrs10930201 on brain structure and cortical function during a
working memory.
Results: We observed a main effect of the genotype on grey matter
density, carriers of the C allele showed reduced gray matter densities
in frontal and insular regions. FMRI analysis revealed no main
effects for the genotype, however C allele carrriers displayed
increased activity in the posterior cingulate cortex.
Conclusions: Activation of PCC has been reported to be agedependent
and enhanced activity is related to poorer performance.
Our results are in line with this suggestion, since only subjects with
the vulnerability allele of rs10930201 displayed a significantly
increased activity of the PCC with increasing age. In summary, our
results illustrate a modulatory effect of the SCN1A polymorphism on
brain morphology and age-related changes in the brain activation in
regions subserving working memory.
120
PP102 ASSOCIATION ANALYSIS OF ANK3 GENE
VARIANTS IN NORDIC BIPOLAR DISORDER AND
SCHIZOPHRENIA CASE-CONTROL SAMPLES
M. Tesli*(1,2), P. Koefoed(3,4), L. Athanasiu(1,2,5), M.
Mattingsdal(5), O. Gustafsson(2,6), I. Agartz(1,7,8), L. Rimol(8), A.
Brown(1,9,10), K. Wirgenes(1,2), E. Jönsson(7), A. Kähler(2,11,12),
T. Werge(13), O. Mors(14), I. Melle(1,2), S. Djurovic(1,2,5), O.
Andreassen(1,2)
1. Institute of Clinical Medicine, University of Oslo 2. Division of
Mental Health and Addiction, Oslo University Hospital 3.
Department of Neuroscience and Pharmacology, University of
Copenhagen 4. Department O, Center of Psychiatry 5. Department of
Medical Genetics, Oslo University Hospital 6. deCODE Genetics 7.
Department of Clinical Neuroscience, Karolinska Institutet and
Hospital 8. Department of Psychiatric Research, Diakonhjemmet
Hospital 9. Department of Biostatistics, University of Oslo 10.
Department of Mathematics, University of Oslo 11. Department of
Genetics, University of North Carolina at Chapel Hill 12. Department
of Medical Epidemiology and Biostatistics, Karolinska Institutet 13.
Research Institute of Biological Psychiatry, Copenhagen 14. Center
for Psychiatric Research, Aarhus University Hospital
*m.s.tesli@medisin.uio.no
Introduction: Several studies have found genetic variants in Ankyrin
3 (ANK3) to be associated with bipolar disorder (BD). We wanted to
investigate the potential association between two previously
identified ANK3 SNPs and BD in a Nordic case-control sample. Due
to evidence of genetic overlap with schizophrenia (SZ), we also
tested for association between these two SNPs and SZ.
Methodology: The two ANK3 SNPs rs10994336 and rs1938526 were
genotyped in a Scandinavian case-control sample (N = 854 BD cases,
1073 SZ cases and 2919 healthy control subjects). Statistical analyses
in the Scandinavian sample were performed with the software
PLINK, using the Cochrane-Mantel-Haenszel test to correct for
population stratification.
Results: When we combined the results from our Scandinavian
sample with the results from an Icelandic sample (N = 435 BD cases,
651 SZ cases and 11491 healthy controls), we found ANK3 SNP
rs10994336 to be nominally significantly associated with BD in this
combined Nordic BD sample (N = 1289 /14105) (P=0.024 using
Fisher`s combined probability test). None of the SNPs were
significantly associated with SZ in the combined Nordic SZ sample
(N = 1724/14410).
Conclusions: These results give further support to the hypothesis that
ANK3 is a BD susceptibility gene and that ion channel dysfunction
may be involved in the underlying pathophysiological mechanisms of
the BD clinical phenotype.

PP103 SIMILARITIES AND DIFFERENCES IN
PERIPHERAL BLOOD GENE EXPRESSION SIGNATURES
OF INDIVIDUALS WITH SCHIZOPHRENIA AND THEIR
FIRST-DEGREE BIOLOGICAL RELATIVES
S. Glatt*(1), W. Stone(2), N. Nossova(3), C. Liew(3), L.
Seidman(2), M. Tsuang(4)
1. SUNY Upstate Medical University 2. Harvard Medical School 3.
GeneNews, Ltd. 4. University of California, San Diego
*glatts@upstate.edu
Introduction: Several studies have evaluated the potential utility of
blood-based whole-transcriptome signatures as a source of
biomarkers for schizophrenia. This endeavor has been complicated
by the fact that individuals with schizophrenia often differ from
appropriate comparison subjects on more than just the presence of the
disorder for example, individuals with schizophrenia typically receive
antipsychotic medications, and have been dealing with the sequelae
of this chronic illness for some time. The inability to control such
factors introduces a considerable degree of uncertainty in the results
to date.
Methodology: To overcome this, we performed a blood-based geneexpression
profiling study of schizophrenia patients (n=9) and
unaffected comparison subjects (n=12), while also including a sample
of nonpsychotic biological siblings of the individuals with
schizophrenia (n=9).
Results: These unaffected biological siblings, who may harbor some
of the genetic predisposition to schizophrenia, exhibited a host of
differences from unaffected comparison subjects, many of which
were shared by their schizophrenic siblings, perhaps indicative of
underlying risk factors for the disorder. Several genes that were
dysregulated in both individuals with schizophrenia and their siblings
related to nucleosome and histone structure and function, suggesting
a potential epigenetic mechanism underlying the risk state for the
disorder. Nonpsychotic siblings also displayed some differences
from comparison subjects that were not found in their affected
siblings, suggesting that the dysregulation of some genes in
peripheral blood may be indicative of underlying protective factors.
Conclusions: This study illustrated the potential utility and increased
informativeness of including unaffected first-degree relatives in
research in pursuit of peripheral biomarkers for schizophrenia.
121
PP104 BLOOD-BASED GENE EXPRESSION SIGNATURES
OF EARLY AUTISM
S. Glatt*(1), M. Tsuang(2), M. Winn(3), L. Lopez(2), K. Pierce(2),
M. Weinfeld(2), C. Carter(2), N. Schork(3), E. Courchesne(2)
1. SUNY Upstate Medical University 2. University of California, San
Diego 3. The Scripps Research Institute
*glatts@upstate.edu
Introduction: One way to combat autistic spectrum disorders
(ASDs) would be to discover their biomarkers, which potentially
could revolutionize diagnosis and management of these
disorders. Here we report the first cross-sectional results of wholetranscriptome
expression profiling in freshly drawn peripheral blood
mononuclear cells (PBMCs) from a longitudinal study of young
children with a variety of neurodevelopmental disorders including
ASDs. Our main objective was to determine the potential utility of a
transcriptomic signature as a biomarker of early autism by
discriminating toddlers with an ASD from those with other
developmental disorders, such as language delay and global
developmental delay, as well as typically developing (TD) toddlers.
Methodology: Enrolled subjects were first diagnosed with (or
identified as being at-risk for) an ASD, language delay, other
developmental delay, or TD between the ages of 12 and 46
months. Each subject’s PBMC mRNA expression profile was
determined by microarray.
Results: Numerous genes with low false-discovery rates
distinguished developmental disorders from each other and from TD
subjects. The 313 genes most reliably changed in AD subjects
relative to two independent TD groups were most strongly associated
with mitotic cell cycle regulation. Other over-represented biological
processes included endopeptidase activity, cerebral cortex
development, microtubule processes, negative regulation of neuron
apoptosis, and neuron migration.
Conclusions: PBMCs may provide a useful source of biomarkers
that are highly specific to the early stages of particular
neurodevelopmental disorders including ASDs. Ongoing
longitudinal analyses will determine if these blood-based biomarker
profiles fluctuate as symptom profiles change over time with
intensive behavioral treatment.

PP105 THE PSYCHIATRIC SUSCEPTIBILITY GENE
CACNA1C AND ITS RELATIONSHIP WITH PERSONALITY
TRAITS, DEPRESSIVE SYMPTOMS, AND COGNITIVE
FUNCTION IN THE GENERAL POPULATION
ECIP
J. Strohmaier*(1), S. Wüst(1), S. Witt(1), V. Nieratschker(1), S.
Meier(1), A. Loerbroks(2), J. Frank(1), T. Stürmer(3,4,5), M.
Amelang(6), M. Rietschel(1), T. Schulze(7)
1. Central Institute of Mental Health, Division of Genetic
Epidemiology in Psychiatry 2. Mannheim Institute of Public Health,
Social and Preventive Medicine, Universitätsmedizin Mannheim,
Medical Faculty Mannheim, Heidelberg University 3. Division of
Pharmacoepidemiology and Pharmacoeconomics and Division of
Preventive Medicine, Brigham and Women's Hospital, Harvard
Medical School 4. Department of Epidemiology, University of North
Carolina, Gillings School of Global Public Health 5. Department of
Internal Medicine VI, University of Heidelberg 6. Institute of
Psychology, University of Heidelberg 7. Department of Psychiatry
and Psychotherapy, University Medical Center, Georg-August-
University
*jana.strohmaier@zi-mannheim.de
Introduction: Recent genome-wide association studies report strong
evidence for an association between the A-allele of rs1006737 in
CACNA1C and bipolar disorder, schizophrenia, and major
depression. We assessed the relationship of rs1006737 with
endophenotypes of these disorders (neuroticism, extraversion, anger
suppression, sense of coherence, dispositional optimism, depression,
perceived social support, psychoticism, working memory, and
declarative memory) within a large longitudinal cohort study. We
further assessed a possible recently described sex-specific effect of
rs1006737 (Dao et al. 2010).
Methodology: A population-based sample of 3793 subjects aged 40-
65 was screened for personality with the Eysenck-Personality-
Inventory (EPI),the State-Trait Anger Expression Inventory (STAXI),
the Sense of Coherence Scale (SOC), the Life Orientation Test
(LOT), for perceived social support questionnaire (SozU), depression
and psychoticism. At 10-years follow-up a subsample of all subjects
aged 70+ was screened for depression and cognition with the
Geriatric Depression Scale (GDS), the Telephone Interview of
Cognitive Status (TICS), the East Boston Memory Test (EBMT), a
Verbal Fluency Test und the Digit- Span Backwards Test. All
subjects were genotyped for rs1006737.
Results: In women, rs1006737 was significantly associated with
depression, neuroticism, sense of coherence, perceived social
support, and psychoticism. G-allele carriers scored higher on
depression, neuroticism, psychoticism, and lower on sense of
coherence and perceived social support than AA-homozygotes. The
strongest association was observed for the resilience factor sense of
coherence (p=0.001 Bonferroni corrected for multiple testing). In
women, rs1006737 was further associated with cognitive function on
a nominal level. Again, we observed an association with the opposite
allele than the previously described risk-allele.
Conclusions: The risk variant rs1006737 is associated with
personality traits and cognitive function in women of the general
population. Two previous findings also reported associations of the
A-allele with low neuroticism (Kühner et al.2010 small healthy
sample), and less baseline depression severity (Casamassima et al.
large clinically depressed sample). The sex-specific effects of
rs1006737 need to be disentangled in larger samples. Our results
suggest that phenotype characterization for psychiatric genetic
association studies need to include the whole continuum from
maladaptive to adaptive/competent functioning.
122
PP106 MICRODELETION IN 10Q23.1 CORRELATED WITH
A SUBTYPE OF SCHIZOPHRENIA WITH SEVERE
DELUSIONS
M. Zeledon*(1,2,3), M. Taub(5), P. Chen(6), A. Pulver(3,4), D.
Avramopoulos(1,3), A. Sawa(3), D. Valle(1)
1. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins
University School of Medicine 2. Predoctoral Training Program in
Human Genetics, Johns Hopkins University School of Medicine 3.
Department of Psychiatry and Behavioral Sciences, Johns Hopkins
University School of Medicine 4. Department of Epidemiology,
Bloomberg School of Public Health 5. Biostatistics, Bloomberg
School of Public Health 6. Department of Medical Genetics, National
Taiwan University Hospital
*mzeledo3@jhmi.edu
Introduction: Schizophrenia (SZ) is a severely disabling psychiatric
disease that affects 1% of the world's population. Patient symptoms
are often categorized as either cognitive, positive (hallucinations,
delusions, bizarre thoughts) or negative (social withdrawal, loss of
motivation, affect flattening, and apathy). In 2003, Fallin et al.
reported a linkage peak (NPL of 4.7) at 10q22 in the Ashkenazi
Jewish (AJ) population. In 2009, Chen et al. followed up with fine
mapping association studies in the AJ and found strong evidence of
association between the quantitative trait "delusion” and three SNPs
in the first intron of NRG3. Two other independent groups have since
replicated these findings, making NRG3 a strong candidate gene for a
subtype of schizophrenia that presents with florid delusions.
Methodology: In this study, we set out to identify causative variants
in the 162 kb LD block covering the 5’ end of NRG3 and containing
the 3 SNPs.
Results: Next-generation Illumina sequencing of 47 AJ SZ patients
at either extreme of the delusion quantitative trait revealed a novel
1.8kb inherited microdeletion 21.5 kb 5’ of NRG3 and located
between two clusters of predicted transcription factor binding sites.
The deletion was found with similar frequencies in the general AJ SZ
(2.7%), AJ Bipolar I (2.6%), and AJ Control (2.8%) populations and
was not found in 346 Outbred SZ cases, leading us to believe it may
be specific to the Ashkenazim. The deletion frequency among the AJ
SZ patients with the highest delusion scores (MAF=10.1% n=69, 7
carrying the deletion) was higher than in patients with the lowest
delusion scores (MAF=0%, n=67) whose deletion frequency was
lower than the frequency in the general AJ SZ population. The
frequency of the deletion between the high and low delusion groups
was also significantly different (p=0.013).Given the difficulties of
classifying patients with intermediate delusion scores into high or
low delusion categories, we tested the correlation between delusion
scores and deletion frequency for 658 AJ SZ patients across the range
of delusion scores, and found this deletion to be significantly
correlated with higher delusion factor scores (p genotype
effects=0.0069).
Conclusions: Due to its location 21.5kb 5’ of the annotated
transcription start site and between annotated transcription factor
binding sites, this deletion may be causative by perturbing regulation
of NRG3 expression. Alternatively, it may have no effect itself but
tag a haplotype containing the causative variant or variants.
Understanding the ways in which variation in this region affect NRG3
expression would allow us to move from these genetic observations
to deciphering the mechanistic pathways that may lead to risk for SZ
or modifications of the SZ phenotype. We are currently testing this
hypothesis in vitro through Dual-Luciferase Assays in HEK239,
HT22 and cultured mouse primary cortical neurons, as well as in vivo
using a LacZ reporter in zebrafish.

PP107 INDEPENDENT EFFECTS OF SEROTONERGIC AND
DOPAMINERGIC POLYMORPHISMS ON TRAIT
IMPULSIVITY
G. Varga*(1), A. Szekely(1), P. Antal(2), P. Sarkozy(2), Z.
Demetrovics(1), Z. Nemoda(3), M. Sasvari-Szekely(3)
1. Institute of Psychology, Eötvös Loránd University 2. Department
of Measurement and Information Systems, Budapest University of
Technology and Economics 3. Institute of Medical Chemistry,
Molecular Biology and Pathobiochemistry, Semmelweis University
*triptamin@gmail.com
Introduction: According to twin studies heritability of trait
impulsivity is approximately 45%. Results from candidate gene
studies are contradictory impulsivity phenotypes measured with
different self report methods demonstrate either the role of the
dopaminergic or the serotonergic neurotransmitter system. Our
present study comprises polymorphisms from both neurotransmitter
systems and investigates association with trait impulsivity.
Methodology: The Barratt Impulsiveness Scale (BIS-11) was used to
assess trait impulsivity in a sample of 687 Caucasian young adults
within the age range of 18-33 years. Analyses of 6 genetic
polymorphisms of the dopaminergic (DRD2, DRD4, COMT) and
serotonergic (SLC6A4, HTR1A, HTR1B) system were carried out
using ANCOVAs with sex as a covariate.
Results: Significant association of a dopaminergic and a serotonergic
polymorphism is reported: lower impulsivity scores characterized the
group carrying the DRD4 7–repeat (p=.006) and the HTR1B 1997 G
alleles (p=.003). Findings endured after Bonferroni correction.
Conclusions: Our study examined the effect of three serotonergic
and three dopaminergic candidate polymorphisms on trait
impulsivity, using a large, ethnically homogeneous sample of
Caucasian young adults from a narrow age range. The presented
results indicate significant and additive effect of two of the studied
polymorphisms. These results support the combined role of
dopaminergic and serotonergic transmitter systems on self-report
impulsivity.
123
PP108 PERIPHERAL BLOOD-EXPRESSION PROFILES AS
BIOMARKERS FOR POSTPARTUM DEPRESSION IN A
HIGH-RISK POPULATION
D. Mehta*(1), L. Kraus(1), M. Rex-Haffner(1), J. Newport(2), Z.
Stowe(2,3), E. Binder(1,2)
1. Max Planck Institute of Psychiatry 2. Emory University School of
Medicine, Department of Psychiatry and Behavioral Sciences 3.
Emory University School of Medicine, Department of Obstetrics and
Gynecology
*divs5@mpipsykl.mpg.de
Introduction: Postpartum depression affects as many as 13% of
women and has a strong negative impact not only on the mother, but
also on the development of the infant. Early detection, possibly by
using biomarkers and timely treatment of the disorder is therefore
very important for both mother and child. The aim of this study was
the identification of biomarkers for postpartum depression in a high
risk population by global assessment of expression changes in
peripheral blood over pregnancy and the early postpartum period and
the characterization of effects of post-partum onset depression on
transcriptional profiles.
Methodology: Multiple measurements from 46 women at high risk
for depressive symptoms during pregnancy and the early postpartum
period were collected in a longitudinal study of peripartum
depression. All women had a history of a mood or anxiety disorder
and included 3 groups. 15 women had postpartum onset depression,
21 showed no depressive symptoms during the time of observation
and 10 women were continuously depressed. Current depressive
symptoms were assessed using the SCID mood module and the Beck
Depression Inventory (BDI). RNA was extracted from whole blood
in Tempus tubes, amplified and hybridized on the Illumina Human
HT12 v4 microarray containing 47,231 probes. Probes were filtered
for background correction and normalized using the VSN
normalization, resulting in 13488 probes for further analysis.
Statistical analysis was performed in R.
Results: Expression changes across pregnancy and the postpartum
period were assessed using mixed model analysis. Transcriptional
profiles of >3000 transcripts were significantly changed across
pregnancy and the early postpartum period after correcting for
multiple testing using the Bonferroni method of correction (p < 3.7 x
10 -6 ). A significant overrepresentation of steroid hormone
transcription factor binding sites within these transcripts was
observed. Comparison of expression profiles in the third trimester of
pregnancy between women with and without postpartum onset
depression using t-tests revealed 496 significant transcripts. Using
expression profiles from these 496 transcripts, women with and
without postpartum depression could be classified with an overall
prediction of 88%, sensitivity of 82.4% and specificity of 93.3%
using the PAMR package.
Conclusions: Our preliminary results indicate that transcriptional
profiles of a large number of transcripts are significantly regulated
across pregnancy, most likely due to the large changes in steroid
hormone levels. Furthermore, there is a subset of transcripts whose
expression in the third trimester of pregnancy is significantly
different between women who will or will not experience postpartum
depression. These transcripts showed a high classification accuracy
and expression levels of these transcripts may serve as potential
biomarkers for peripartum depression. Validation of these results
using real-time PCR and addition of more samples to the current
dataset to add power to the study are currently underway. Our data
suggest that a risk for postpartum depression might be detected as
early as the last trimester of pregnancy allowing timely prevention
and treatment strategies.

PP109 MITOCHONDRIAL DYSFUNCTION IN AUTISM
A. Ayyappan*(1), K. Nakamura(2), T. Ismail(2), S. Suda(3), K.
Yamada(4), Y. Iwayama(4), T. Yoshikawa(4), N. Takei(1), N.
Mori(1,2)
1. Research Center for Child Mental Development, Hamamatsu Univ
Sch Med 2. Dept of Psychiatry & Neurology, Hamamatsu Univ Sch
Med 3. Dept of Psychiatry, Jichi Med Univ 4. Laboratory for
Molecular Psychiatry, RIKEN Brain Sci Inst
*anitha@hama-med.ac.jp
Introduction: Mitochondria serve as the energy powerhouses of
eukaryotic cells since they generate most of the adenosine
triphosphate (ATP), the source of chemical energy in cells. Defects
in brain energy metabolism resulting from mitochondrial dysfunction
(MtD) have been implicated in autism, as evidenced by diminished
levels of ATP in autistic brains, and mitochondrial abnormalities that
have been observed in the animal models of this disorder. Abnormal
energy metabolism may lead to damage to brain cells, resulting in
cognitive-, language- and behavioral- abnormalities. Previous studies
of MtD in autism had been restricted to common enzymes involved
in energy metabolism. Most of the genetic studies were based on
mutations in the mitochondrial DNA (mtDNA). However, despite the
mtDNA, the genomic DNA encodes several essential proteins
involved in mitochondrial activities. We carried out a comprehensive
study of the role of MtD in the pathogenesis of autism. Expressions
of genes involved in diverse mitochondrial functions (e.g.
mitochondrial biogenesis, transport and energy production) were
compared between the postmortem brains of autism patients and
healthy controls. The genes that showed altered expressions in autism
were further checked for association with this disorder, in a familybased
study.
Methodology: Frozensamples from autism patients (n=8) and
controls (n=10), belonging to the following brain regions, were
obtained from the Autism Tissue Program, U.S.A., (i) anterior
cingulate gyrus (ACG 8 autism, 13 controls), (ii) motor cortex (MC 7
autism, 8 controls), and (iii) thalamus (TH 8 autism, 9 controls). The
Human Mitochondria PCR Array (SABiosciences, MD, USA), which
profiles the expressions of 84 genes involved in diverse functions of
mitochondria, was used to quantify gene expression based on SYBR
Green real-time qRT-PCR method. For the association study, we
analyzed DNA samples from 841 Caucasian- and 188 Japanese-
families. Single nucleotide polymorphisms (SNPs) for the study were
selected from the data of International HapMap Project. TaqMan
method of SNP genotyping was used to score the SNPs. Family
Based Association Test (FBAT) was used to examine the association
of SNPs with autism.
Results: Several genes showed altered expressions in the brains of
autism patients compared to controls. Among these, metaxin 2
(MTX2 2q31.1), neurofilament, light polypeptide (NEFL 8p21.2) and
solute carrier family 25, member 27 [SLC25A27, also known as
uncoupling protein 4 (UCP4) 6p12.3] showed consistently reduced
expressions in the ACG, MC and TH of autism patients compared to
controls. Further, we checked the associations of MTX2, NEFL and
SLC25A27 with autism in Caucasian- and Japanese- family samples.
NEFL (rs2979704 in Exon 4 UTR) showed a significant association
(p=0.038) with autism in the Caucasian samples.
Conclusions: This is the first comprehensive study of MtD in autism.
Considering our results, NEFL is a promising candidate gene for MtD
in this disorder. NEFL is one of the most abundant cytoskeletal
components of neurons. It plays a pivotal function in the assembly
and maintenance of axonal cytoskeleton, playing a role in regulating
neuronal development, specifically neurite outgrowth. NEFL is
located in 8p21.2, which has been identified as a potential
susceptibility locus in a previous genome-wide association study.
Furthermore, chromosome 8p has been identified as a potential hub
for developmental neuropsychiatric disorders.
124
PP110 INVESTIGATING THE RELATIONSHIP
BETWEEN IRON AND IQ OR DEPRESSION
IN ADOLESCENTS
N. Mills*, N. Hansell, M. Wright, J. Whitfield, N. Martin, N. Wray
Queensland Institute of Medical Research
*natalie.mills@qimr.edu.au
Introduction: Inflammatory markers, including ferritin, C-reactive
protein, and pro-inflammatory cytokines have been implicated in the
etiology of psychiatric disorders such as major depressive disorder
they have also been related to measures of cognition. Only a few
studies have investigated this relationship and these studies have
relatively small sample size and have rarely focussed on adolescents.
Our objective is to investigate the phenotypic and genetic relationship
between measures of circulating levels of iron (ferritin, transferrin,
and saturation of transferrin) and of IQ and depressive symptoms in
adolescents. (Transferrin saturation is a measure of the degree to
which transferrin (iron transport protein) receptors are occupied by
iron).
Methodology: Data was collected from the ongoing Brisbane
Adolescent Twin Study, based at Queensland Institute of Medical
Research. Here, we report data from twin adolescents, all
aged greater than 15.0 years but less than 17.0 years. The sample
size comprised between 1,434 and 2,463 twin adolescents, depending
on the measure. Full-scale IQ (FIQ) was assessed by the
Multidimensional Aptitude Battery (MAB) and can be expressed on
the sub-scales of verbal IQ (VIQ), and performance IQ
(PIQ). Depressive symptoms were extracted from the Somatic and
Psychological Health Report (SPHERE) and a sum score of item
response was created for each individual. A log transformation was
applied to the ferritin measures. Data was analysed using the
statistical program Mx and the sib-pair program.
Results: The measures of iron, transferrin, transferrin saturation and
log10 of ferritin are all highly heritable, with heritabilities of 0.67 for
transferrin, 0.77 for transferrin saturation, 0.73 for iron, and 0.75 for
log10 of ferritin. Heritabilities of FIQ, VIQ and PIQ were found to
be 0.66, 0.59, and 0.68 respectively. The heritability of total
SPHERE score was 0.34. Analyses about the phenotypic and genetic
relationship between these measures and depression and cognition
measures are ongoing.
Conclusions: We aim to provide insight into the relationship
between inflammatory markers and depression and cognition.

PP111 THE ASSOCIATION OF THE NICOTINIC
ACETYLCHOLINE RECEPTOR (CHRNα5) GENE AND THE
BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) GENE
WITH DIFFERENT ASPECTS OF SMOKING BEHAVIOR
E. Breetvelt*(1,2), M. Numans(2), W. Hoeben(1), E. Strengman(3),
J. Luyxk(1), M. Aukes(1,2), S. Bakker(1), R. Kahn(1), R.
Ophoff(1,3,4), M. Boks(1,2)
1. a) Rudolf Magnus Institute of Neuroscience, Department of
Psychiatry, University Medical Center Utrecht 2. b) Julius Center for
Health Sciences and Primary Care, University Medical Center
Utrecht 3. c) Department of Medical Genetics, University Medical
Center Utrecht, Utrecht 4. d) Center for Neurobehavioral Genetics,
University of California Los Angeles
*e.j.breetvelt@umcutrecht.nl
Introduction: Background: Recent studies show that different
aspects of smoking behavior are associated with the alpha-5 subunit
of the nicotinic acetylcholine receptor (CHRNA5) gene and the gene
coding for brain-derived neurotrophic factor (BDNF). This raises the
question whether the amount of cigarettes used per day has a
different genetic background than smoking initiation and what other
smoking phenotypes may be relevant. Aim: Replicate these recent
findings in a large population based sample.
Methodology: We investigated the association with smoking
initiation and the number of cigarettes used per day as well as
additional smoking phenotypes in a population based sample of 2.166
participants of Dutch origin.
Results: rs16969968 in the CHRNA5 gene was associated with the
amount of nicotine use and in particular smoking 25 cigarettes or
more per day. rs6265 in the BDNF gene was not associated with
smoking initiation. Instead, in this sample this SNP was associated
with smoking cessation.
Lifetime Current
smoking smoking
Cigarettes
Smoking
smoked per
cessation
day
AA 52.8% 21.4% 59.4% 16.2 9.6 20.0%
Smoking 25
(SD) cigarettes or more
per day
p-value 0.43 0.80 0.83 0.02 0.01
AG 54.0% 23.7% 56.3% 13.8 8.6 13.5%
p-value 0.51 0.42 0.17 0.36 0.05
GG 55.5% 22.2% 60.4% 13.1 8.5 7.7%
reference reference reference reference reference
Total 54.4% 22.8% 41.5% 13.7 8.7 11.6%
table 1
Results for CHRNA5 rs16969968. P-values were calculated using
homozygotic wild-type as reference group. P-values below 0.05 are
highlighted in bold.
Ever
smoking
Current Smoking
smoking cessation
Cigarettes
smoked per
day
Smoking 25
(SD) cigarettes or more
per day
CC 62.5% 13.6% 77.8% 9.5 5.8 0.0%
p-value 0.21 0.10 0.02 0.14 n.a.
CT 53.1% 25.0% 53.2% 14.2 8.9 12.0%
p-value 0.42 0.14 0.03 0.51 0.99
TT 54.9% 22.8% 60.0% 13.5 8.6 11.7%
reference reference reference reference reference
Total 54.4% 22.8% 41.5% 13.7 8.7 11.6%
table 2
Results for BDNF rs6265. p-values were calculated using
homozygotic wild-type as reference group. P-values below 0.05 are
high-lighted in bold.
Conclusions: Overall the results confirm the involvement of the
nicotinic acetylcholine receptor gene in modifying the amount of
nicotine use and further suggest involvement of the brain-derived
neurotrophic factor gene in smoking behavior.
125
PP112 ASSOCIATION STUDY AMONG THREE BDNF
VARIANTS IN MEXICAN PATIENTS WITH OCD: CASE-
CONTROL AND FAMILY-BASED STUDIES
L. Márquez*(1), B. Camarena(2), C. Lóyzaga(1), S. Hernández(2),
L. Vargas(1), I. Vargas(2), A. Aguilar(2), H. Nicolini(3)
1. Clinic of Obsessive-Compulsive Disorder and Spectrum Disorders,
National Institute of Psychiatry Ramón de la Fuente Muñiz 2.
Department of Psychiatric Genetics, National Institute of Psychiatry
Ramón de la Fuente Muñiz 3. Autonomous University of Mexico
City
*pita.rocker@gmail.com
Introduction: Obsessive-compulsive disorder (OCD) is a psychiatric
disorder whose etiology is not yet known, even though it is clear that
genetic factors play an important role. In 2003, an association
between the Brain-Derived Neurotrophic Factor (BDNF) and OCD
was described in a family-based association study, but those results
has not been replicated to date, although some findings support the
theory that BDNF may be implicated in the molecular etiology of
OCD. In this study, we investigate the role of three variants of the
BDNF gene (rs6265, rs1519480 and rs7124442) by single SNP and
haplotypes analysis in OCD Mexican patients using a case-control
and family-based association design.
Methodology: Three polymorphic variants of BDNF gene were
genotyped in a control group (n=283), OCD subjects (n=260) and
first degree relatives of 109 OCD subjects (n=185). All samples were
genotyped using TaqMan allelic discrimination assays. Single SNP
and haplotype analyses were conducted to determine association
between BDNF variants and OCD. Finally, clinical information (age
at onset, Yale-Brown Obsessive-Compulsive Severity Scale and
Symptom Checklist, comorbidity, family history of psychiatric
disorders) were obtained in 143 OCD patients for which statistical
analysis was conducted in order to investigate whether any genetic
variant was associated with a specific clinical phenotypes in OCD.
The diagnosis of OCD and the clinical assessment were evaluated by
psychiatrists experts in OCD.
Results: Single SNP analysis in case-control study showed a
statistically significant association between rs6265 and OCD. In
particular, we observed a high frequency of Val/Val genotype and
Val allele in OCD patients compared with control group ( χ 2 =26.6,
p=0.0000 χ 2 =28.5, p=0.0000, respectively). Also, analysis of
rs1519480 showed a high frequency of G allele in OCD patients
compared with the control group ( χ 2 =25.8, p=0.0000). There was no
statistically significant association between the rs7124442 and OCD.
Haplotype analysis showed that A-A-T (rs6265-rs1519480rs7124442)
was found statistically more frequent in OCD group than
control group (p=0.0041), showing a 2.8-fold increased risk of OCD.
Also, a low frequency of A-G-T haplotype was observed in OCD
patients (p=0.0024).
When age at onset of OCD, symptom dimensions, symptom severity
and gender was analyzed in single locus and haplotype-based
analysis, no significant association between any variant or haplotype
was observed, but an increased risk of the contamination/cleaning
dimension for males carriers of the Val allele of rs6265 (p=0.0096).
Finally, the family-based association study showed no significant
differences in the transmission of any variant.
Conclusions: We replicated the association between Val allele of
rs6265 BDNF gene polymorphism and OCD. We found significant
association of rs1519480 in OCD patients compared with a control
group. Finally, we observed a high risk haplotype (A-A-T) in OCD
patients and a protective A-G-T haplotype for OCD. Interestingly, the
risk to develop OCD could be dependent of being a carrier of A
variant of rs1519480, region that has never been analyzed in OCD.
Therefore, our findings suggest that BDNF gene could be related to
the development of OCD.

PP113 ASSOCIATION OF EVENT-RELATED DELTA BAND
OSCILLATIONS AND SINGLE NUCLEOTIDE
POLYMORPHISMS IN THE CHOLINERGIC NICOTINIC
RECEPTOR GENE LOCUS (CHRNA6-CHRNB3) ON
CHROMOSOME 8
N. Manz*(1), M. Rangaswamy(1), S. Kang(1), A. Goate(2), K.
Bucholz(2), J. Wang(2), J. Rice(2), L. Almasy(3), J. Tischfield(4), M.
Schuckit(5), J. Kramer(6), H. Edenberg(7), L. Bierut(2), B.
Porjesz(1)
1. SUNY Downstate Medical Center 2. Washington University
School of Medicine 3. Texas Biomedical Research Institute 4.
Rutgers University 5. University of California San Diego 6.
University of Iowa 7. Indiana University School of Medicine
*nmanz@hbnl.downstate.edu
Introduction: Brain electrical activity recorded using non-invasive
electroencephalography (EEG) provide sensitive measures of brain
function with exquisite temporal resolution during cognitive tasks.
Extensive existing literature indicates that the P3 component of the
event-related potential (ERP) is reduced in abstinent alcoholics and in
offspring at risk. More recently it has been reported that the theta and
delta event-related oscillations (EROs) underlying P3 are also
reduced in alcoholics and their offspring; theta has a frontal
topography and is related to attention, while delta has a posterior
topography and is related to decision making processes. These ERO
endophenotypes are highly heritableand more proximal to gene
function than diagnosis, providing a powerful strategy in searching
for genes in psychiatric disorders, such as alcoholism. In the
Collaborative Study on the Genetics of Alcoholism (COGA) we have
found that these ERO phenotypes have been useful in gene
identification associated with a predisposition to develop alcohol
dependence and related disorders. There is evidence in the literature
that nicotinic receptor genes in the CHRNA6-CHRNB3 locus are
associated with smoking and alcohol behaviors.
Methodology: EROs in the delta band (1-3 Hz) were calculated from
EEG recordings during a visual oddball task in 988 adolescents and
young adults (12-25 years) from COGA alcoholic and control
families (643 European-American, 247 African-American, 98 Others)
along with drinking and smoking variables. Analyses of delta EROs
at the midline posterior lead where they are maximum and single
nucleotide polymorphisms (SNPs) in the cholinergic nicotinic
receptor gene cluster CHRNA6-CHRNB3 was performed using a
linear regression model for a case-control study with 263 subjects
from families affected with alcoholism and 725 subjects from control
families.
Results: We find evidence for several SNPs in the CHRNA6-
CHRNB3 locus on chromosome 8 to be significantly associated (FDR
corrected p=0.02-0.004) with delta EROs at the posterior midline
electrode (Pz) in response to the target stimulus.
Conclusions: These findings support a role for the cholinergic
nicotinic receptor genes on chromosome 8 (CHRNA6 and CHRNB3)
in the genetic predisposition towards alcoholism, and underscore the
utility of brain oscillations and the endophenotype approach in
understanding complex psychiatric disorders.
126
PP114 CORTICOTROPIN-RELEASING HORMONE
RECEPTOR1 GENE SNPS INTERACT WITH STRESS TO
PREDICT DEPRESSION LONGITUDINALLY
M. Moore*(1), C. Van Hulle(1), E. Shirtcliff(2), M. Essex(1), K.
Lemery-Chalfant(3), H. Goldsmith(1)
1. University of Wisconsin-Madison 2. University of New Orleans 3.
Arizona State University
*mnmoore@wisc.edu
Introduction: The genetic diathesis-environmental stress model
posits that studying either environmental or genetic factors in
isolation is likely to prove less fruitful than studying the interplay
between the two (Rutter, 2005). The importance of stress in
precipitating depressive symptoms has led to a focus on the
hypothalamic- pituitary-adrenal (HPA) axis in depression’s
etiology. Corticotropin-releasing hormone (CRF) is a neuropeptide
that regulates activity of the HPA axis. Polymorphisms of
corticotropin-releasing hormone receptor1 (CRHR1), the gene that
codes for the CRF 1 receptor, are thus likely to have an impact on
HPA axis activity (Binder & Nemeroff, 2010). Although CRH
receptors have received only modest research attention, CRHR1
polymorphisms appear to be associated with the risk for depression in
adult samples (Liu et al., 2006; Bradley et al, 2008). Patterns of
family resemblance for afternoon cortisol levels are strongly
influenced by environmental (not genetic) factors and thus may act as
a proxy of family stress (Schreiber et al., 2006; Ellenboge et al.,
2004; Burke et al., 2005). We examined two allelic variants in the
CRHR1 gene and their interaction with afternoon cortisol to predict
depressive symptoms longitudinally from middle childhood to early
adolescence.
Methodology: Participants were from a longitudinal, birth recordbased
twin panel; relevant data were available for 493 Caucasian
individuals (48.9% female). At mean age 8.02 years (SD=.80),
participants and their parents completed assessments that included
diagnostic interviews and DNA collection via
buccal swabs. Participants also provided saliva samples, collected
between 1500h and 1900h on three consecutive days, which were
used for cortisol assays. At mean age 13.40 years (SD=1.30)
participants again completed diagnostic interviews to assess
depressive symptoms.
Results: For both rs242938 and rs242939 (which were in strong
linkage disequilibrium), the homozygous minor allele group was
combined with the heterozygous group and compared to the
homozygous major allele group (for rs242938, T carriers [n=81] were
compared to CC homozygotes [n=409]; for rs242939, G carriers
[n=59] were compared to AA homozygotes [n=399]). We tested
main and interactive effects of the polymorphisms and afternoon
cortisol level on depressive symptoms using generalized estimating
equations to account for the paired nature of twin data, and included
gender as a covariate. We observed main effects for both
polymorphisms, such that minor allele carriers reported higher
depressive symptoms in adolescence (for rs242938, b=.36, z=2.03,
p=.04; for rs242939, b=.46, z=2.14, p=.03). In interaction with
afternoon cortisol, rs242938 significantly predicted later depression,
b=6.83, z=3.05, p=.002, such that T carriers with higher afternoon
cortisol levels at age 8 reported higher depressive symptoms in
adolescence. A similar interaction was found for G carriers of
rs242939, b=7.72, z=2.66, p=.008. For both polymorphisms, family
stress was a significant predictor of later depression for minor allele
carriers (for rs242938, p

PP115 A GENOME-WIDE ASSOCIATION STUDY OF
BIPOLAR DISORDER AND CO-MORBID MIGRAINE:
REPORTING ASSOCIATION WITH THE GENE
NEUROBEACHIN (13Q13.2)
K. Oedegaard*(1,2,3), S. Johansson(4,5), T. Greenwood(3), O.
Fasmer(1,2), H. Akiskal(3), B. Genome Study(6), J. Haavik(4), J.
Kelsoe(3)
1. MoodNet, Haukeland University Hospital, Psychiatric Division 2.
University of Bergen, Department of Clinical Medicine, Section of
Psychiatry 3. Department of Psychiatry, University of California 4.
Department of Biomedicine, University of Bergen 5. Center for
Medical Genetics and Molecular Medicine, Haukeland University
Hospital 6. Bipolar Genome Study
*keti@haukeland.no
Introduction: Both bipolar disorder (BPAD) and migraine are highly
heritable disorders with considerable non-genetic components. The
co-morbidity between migraine and BPAD has been demonstrated in
a large amount of epidemiological and clinical studies, and there is
also some evidence for shared genetic vulnerability.
Methodology: To identify susceptibility factors for the
BPAD/migraine phenotype, we conducted a GWAS in 1157 cases
with bipolar disorder collected through the NIMH Genetics Initiative
for Bipolar Disorder and genotyped at 1M SNPs by the Translational
Genomics Institute (TGEN) in Phoenix (TGEN1). We compared
BPAD patients without migraine (n= 765) to BPAD patients with
migraine (n=392).
Results: The strongest evidence for association was found for several
SNPs on chromosome 13 in a region encompassing the gene
Neurobeachin with the strongest signal at rs1160720 (P= 5.96x 10-8).
Conclusions: We hypothesised that the subgroup of patients
presenting combined symptoms from two different brain disorders
associated with disturbances in neuronal membrane passage (i.e
migraine and BPAD) might reflect a complex neurodegenerative
phenotype that could share an underlying genetic susceptibility. The
findings of this study suggest that NBEA may predispose to a
combined phenotype of bipolar disorder and migraine headache,
which comprises a subset of bipolar patients.
127
PP116 THE GENETICS OF DEPRESSION SUBGROUPS AND
DIMENSIONS
R. Power*, R. Uher, P. McGuffin, C. Lewis
Institute of Psychiatry
*robert.r.power@kcl.ac.uk
Introduction: Depression has a lifetime prevalence of 16% yet as a
phenotype it shows variation in symptoms and severity and differing
response to treatment. The lack of replicable genetic findings in
depression further suggests that what is defined as one group
clinically may be heterogeneous. Using the combined data from three
depression studies (DeCC, DeNT, and GENDEP) totalling 3300
cases, we sought to create a more homogenous grouping of classes
for genome wide analysis.
Methodology: Three methods were used to explore the symptom
profiles of the individuals, based on 16 binary symptom scores.
Firstly, latent class analysis (LCA) was used to explore a categorical
view of depression, aiming to empirically replicate recognized
subtypes of depression (melancholic, atypical, etc.). Secondly, factor
analysis (FA) was used to construct quantitative traits, aiming to
provide a more dimensional view of depression. Lastly, factor
mixture analysis (FMA) was used to create latent classes within
which individual variation could be accounted for by factors. As even
if depression is made up of one or more quantitative traits, the
selection of individuals into case control studies would likely result in
class-like distributions.
Results: All three methods produced similar results. LCA resulted in
a 4 class model best fitting the data. The classes could be defined as a
moderate depression class, a severe class, and two classes
intermediate in severity, one with atypical rather than typical features
(increased appetite and sleep, rather than a decrease). FA provided
the best fitted model with 2 factors, and parallel analysis showed
most information was held in these first two factors. The first factor
was loaded on all symptoms, particularly those crucial to diagnosis of
depression (anhedonia, low mood, etc.), suggesting it represented a
score of overall severity. The second factor's loadings reflected the
link between eating and sleeping symptoms, i.e. that overeating
correlated with oversleeping, and the reverse. FMA showed the best
fit model contained 4 classes and 2 factors, and gave similar results to
the LCA model. GWAS analysis of the individuals in each of the 4
LCA classes against 1600 controls identified several novel
associations at suggestive significance, but none reaching genomewide
significance. The severe class (n=620) had 5 SNPs reaching
suggestive significance. This included one SNP in the q14 region of
chromosome 2, one in the in the q26 region of chromosome 3, and
three on chromosome 5. The class with atypical features of
depression (n=710) showed association with one SNP in the p25
region of chromosome 3. No SNPs were found to be associated with
the other two classes.
Conclusions: The LCA and FA gave empirical evidence for two
distinctions in the diagnosis of depression: overall severity and the
correlation of eating and sleeping symptoms. Sadly the reduction in
heterogeneity failed to lead to GWAS findings of genome wise
significance. The next stage of analysis will be to re-analyse with
weighting of individuals by their probability of belonging to each
class. This should provide a better integration of the FMA results and
GWAS data, and hopefully strengthen the suggestive association
findings. We also plan to evaluate the heritability of these classes.
We will use confirmatory analysis of class allocation in 1600 siblings
of the DENT sample that were not included in class construction.
Identification of heritable symptom patterns in depression should
produce more heterogeneous populations and diagnoses, which in
turn can be used to improve power in GWAS.

PP117 THE NUMBERS SENSE AND ITS RELATIONSHIP
WITH MATHEMATICAL ABILITY AND DISABILITY
M. Tosto(1), Y. Kovas(1,2), R. Plomin*(2)
1. Psychology Department, Goldsmiths College 2. Social, Genetic
and Developmental Psychiatry Centre, Institute of Psychiatry
*robert.plomin@kcl.ac.uk
Introduction: Number Sense refers to the untaught, non-verbal
abilities to estimate and approximate numerosities. These abilities
seem to be specific to the mathematical domain. Studies have shown
that individual differences in Number Sense abilities positively relate
to individual variation in mathematical tests scores and achievement.
To date, the nature of these relationships is largely unknown. As part
of the Twins Early Development Study (TEDS), we present the first
genetically sensitive investigation looking into the aetiology of the
Number Sense and the relationship between Number Sense and
mathematical ability and mathematical disability.
Methodology: A pilot study was conducted to assemble and validate
an on-line battery comprising seven tests designed to assess the
specific ability to approximate numerosity, numerical magnitude,
non-verbal spatial memory, speed of processing, and a range of
mathematical skills. All tests were age appropriate for 16 year olds.
The battery is currently being administered to the TEDS as part of the
assessment at 16-years of age. 2,274 twins belonging to the first
cohort have already completed the assessment. More data will be
available when the second cohort will start testing at the end of
August 2011. The twins also completed the PISA (Programme for
International Student Assessment) questionnaires measuring attitude,
interest, self efficacy and time spent on mathematics.
Results: Preliminary analysis on the data from the first cohort shows
that Mathematical performance is significantly predicted by Number
Sense and general cognitive abilities measures. The genetic analysis
of mathematical performance at 16 showed the pattern similar to
previous ages, with a moderate (.6 - .5) genetic component, almost
nonexistent shared environment and high (.5 - .7) non-shared
environment. The first genetic analysis on the Number Sense
measures showed a surprisingly low heritability, and a large nonshared
environmental component. Among the PISA questionnaire,
mathematical ability was related to mathematics self-efficacy and the
time spent doing mathematical activities. More detailed behavioural
and quantitative genetic analyses are currently under way.
Conclusions: To date the Number Sense was thought to have
evolutionary origin, however the study presented in this paper is the
first to show that these abilities have, in fact, low familiality. The
results of this study show that mathematics remains a heritable trait at
16 years of age. Multivariate genetic analyses will uncover the
aetiology of the co-variance among the traits. The results of this study
will help to understand better the mechanisms underlying
mathematical variation and will help explaining the development of
mathematical disability.
128
PP118 AUTISM AND SCHIZOPHRENIA IN 22Q11DS, TRUE
PLEIOTROPY OR DIFFERENT WAYS OF LOOKING AT
THE SAME PHENOTYPE
J. Vorstman*(1), E. Breetvelt(1), E. Chow(2,3), A. Bassett(2,3)
1. Rudolf Magnus Institute of Neuroscience, Department of
Psychiatry, University Medical Center Utrecht 2. Clinical Genetics
Research Program, Centre for Addiction and Mental Health 3.
Department of Psychiatry, University of Toronto
*j.a.s.vorstman@umcutrecht.nl
Introduction: An increasing number of structural genomic variants,
in particular copy number variants (CNVs), is identified as large
effect risk factors for neuropsychiatric diseases. Notably, while at
first specific CNVs were thought to be associated with either
schizophrenia or autism spectrum disorders (ASDs), subsequent
studies reported the occurrence of many of these CNVs in both
disorders. When one genetic variant can lead to two or more distinct
phenotypes, the concept of pleiotropy can be applied. For instance,
deletions at 15q13.3, 17q12, 16p11.2, and 22q11.2, as well as
deletions of NRXN1 and duplications of VIPR2 are all associated
with both schizophrenia and ASDs. How can we better understand
this pleiotropy? Here, the question is whether the observation of both
ASDs and schizophrenia in carriers of a specific CNV is to be
considered true pleiotropy or rather as the same phenotype or
expressions of the same pathological process, i.e. schizophrenia,
observed at different stages. The 22q11.2 deletion syndrome
(22q11DS) occurs relatively frequently allowing for sufficiently
powered studies to examine the neuropsychiatric pleiotropy observed
in relation to many CNVs. We hypothesized that in 22q11DS, autistic
features during childhood are a precursor manifestation of
schizophrenia. Therefore ASD in patients with 22q11DS would be
associated with higher rates of subsequent schizophrenia in
adulthood.
Methodology: We have tested this hypothesis by studying a cohort
of 78 adult 22q11DS patients who underwent thorough and
standardized psychiatric evaluation (as described previously)
allowing a lifetime diagnosis of schizophrenia to be made or ruled
out. In addition, caregivers of these patients were asked to
retrospectively report ASD symptoms of their child during childhood
using the social responsiveness Scale (SRS) and the Social
Communication Questionnaire lifetime (SCQ). We compared mean
SRS T-scores in 22q11DS patients with and without schizophrenia,
and generated 95% Confidence Intervals (CIs) through a
bootstrapping procedure (n = 1000). A Mann-Withney-Wilcoxon test
was used to test differences between the two groups. Using the
questionnaire data in a dichotomous fashion, we applied a binary
logistic model with cut-off scores of 12 and 15 for the SCQ and 60
for the SRS T-score as predictors. We calculated Odds Ratio (ORs)
and their 95%CIs, entering age, IQ and sex as covariates.
Results: Mean SRS scores and 95%CIs were virtually identical in
22q11DS patients with and those without schizophrenia (p=0.36).
Results from the logistic regression demonstrated no significant
predictive effect of ASD as a dichotomous variable measured by the
SRS or the SCQ.
Conclusions: The results demonstrated that ASD during childhood is
not associated with an increased risk for schizophrenia later in life in
22q11DS patients. The average SRS scores were highly similar
between those with and those without schizophrenia suggesting that
even small effect sizes are unlikely. The previously reported
increased rates of both schizophrenia and ASD in 22q11DS patients,
together with the absence of any association between these two
disorders in the current study, lend evidence to the possibility that
ASD and schizophrenia should be considered as two distinct,
pleiotropic neuropsychiatric consequences of the 22q11.2 deletion.

PP119 ANTIPSYCHOTIC TREATMENT AND COPY
NUMBER VARIATIONS - A PILOT STUDY
C. Skjødt*, A. Ingason, K. Jakobsen, T. Hansen, J. Thygesen, L.
Duong, T. Werge
Research Institute of Biological Psychiatry, Mental Health Center Sct
Hans, Copenhagen University Hospital
*celina@regionh.dk
Introduction: The identification of multiple genetic high risk factors
of schizophrenia seems to suggest the existence of a corresponding
number of etiological subtypes of the disorder subtypes that might
well be characterized by correspondingly distinct profiles of response
to medical therapy. To test this hypothesis, we conducted a blinded,
matched case-control pilot study to examine the correlation between
effect of antipsychotic treatment and CNV status.
Methodology: 12 schizophrenia patients carrying CNVs associated
with schizophrenia were matched one-by-one on age and gender to
12 schizophrenia patients without CNVs all 24 patients were
originally ascertained together to the same sample. Clinical data from
ten years of medical records (2000-2010) and data from the
comprehensive, national health registers were collected for all 24
patients. Medical records were rated without knowledge of CNV
status.
Results: Paired analysis showed that body mass index, smoking,
CYP2D6 phenotype, substance abuse, suicidal behavior and
habitation were similar between the two groups. The CNV carriers
had experienced fewer positive antipsychotic drug trials than the noncarriers
(1.42±1 vs. 2.08±1) and more antipsychotic drug trials
altogether (3.42±2.31 vs. 2.72±1.60), corresponding to a significant
lower success rate per drug trial (p=0.019). Also, we found an
indication that CNV carriers might have an earlier age of onset (p =
0.086) and were more hospitalized during their illness, measured as
percentage of time spent in hospital during their illness (p = 0.062). A
sample size of 48 patients with the same outcome would have yielded
significant results for these last two trends.
Conclusions: These observations seem to support general
expectations that CNV-carrying patients may have an earlier onset of
illness which also could explain their greater deal of hospitalization
and poorer effect of antipsychotic treatment. A larger study is needed
to investigate these findings further importantly a sample only twice
as large would have sufficient power to capture significant
differences in these variables.
129
PP120 RELEVANCE OF RECENTLY-IDENTIFIED
SCHIZOPHRENIA RISK VARIANTS TO A CHILD AND
ADOLESCENT CLINICAL POPULATION
A. Doyle*(1,2,3,4), E. Braaten(2,3), C. O'Dushlaine(4), D.
Ruderfer(1,4), D. Toner(1), N. Doty(2,3), K. Chambert(4), J.
Moran(4), E. Hill(1), B. Neale(1,3,4), S. Purcell(1,2,3,4), J.
Smoller(1,2,3,4), P. Sklar(5)
1. Center for Human Genetics Research, Massachusetts General
Hospital 2. Department of Psychiatry, Massachusetts General
Hospital 3. Harvard Medical School 4. Stanley Center for Psychiatric
Research at the Broad Institute of Harvard & MIT 5. Mount Sinai
School of Medicine
*aedoyle@partners.org
Introduction: It is well- documented that the risk mechanisms
leading to severe adult psychopathology begin to unfold in childhood
and adolescence and that treatment prior to the onset of disorder
reduces morbidity and mortality. Yet, there are multiple hurdles to
effective early identification and intervention in the field of child
psychiatry. Given that the initial clinical manifestations of conditions
such as schizophrenia and bipolar disorder are far more common than
conversion to illness, enumerating signs and symptoms has limited
potential to distinguish youth at greatest risk for poor outcome from
those on a more benign course. The search for objective criteria by
which to determine risk is further hindered by imprecise
measurement tools and uncertain diagnostic boundaries.
Unprecedented progress in the past two years in the identification of
genetic risk variants for schizophrenia and bipolar disorder creates
the potential for improved prognostic algorithms and early and
personalized intervention by incorporating genetic data into clinical
practice. Yet, the probabilistic nature of genetic risk in multifactorial
phenotypes and the shared etiology among disorders suggests that the
pathways from genes to behavior will be complex, with risk variants
likely to index traits that cut across what are currently considered
different conditions. Thus, there is considerable work to be done
before the translation of such findings to patients will rest on solid
empirical ground.
Methodology: We are merging state-of-the-art human genetics
methods with high-quality, comprehensive assessment of
neurocognitive and psychiatric quantitative traits in child and
adolescent outpatients being evaluated in a new pediatric
neurpsychology clinic at Massachusetts General Hospital. Currently,
we are aiming to describe the full phenotypic spectrum of replicated
risk variants from the recent literature. Our eventual goal is to map
trajectories to major adult psychiatric illness. As proof of concept for
this work, we have obtained genomewide genotyping and extensive
phenotyping on a pilot sample of 74 outpatients from this clinic using
an Illumina 2.5 v1 array. We explored genomewide CNV burden
using PennCNV and extrapolated a polygenic schizophrenia risk
score based on GWAS data from the International Schizophrenia
Consortium.
Results: We have detected both large (greater than 500kb) and small
(between 100 and 30kb) structural variants in regions highlighted in
the recent schizophrenia literature in clinic patients, some of whom
already show signs of severe psychiatric illness. We have also
documented an association between CNV burden and specific clinical
phenotypes. Additionally, we have established the relevance of a
polygenic schizophrenia risk score to the sample, which distinguishes
patients as a whole from healthy adult controls.
Conclusions: Results speak to the promise of studying variants from
the recent psychiatric genetics literature in well-characterized child
and adolescent clinical samples that can be followed longitudinally.

PP121 KYNURENE METABOLITE LEVEL (KYNA)
ALTERATION IN BIPOLAR DISORDER PSYCHOSIS AND
ASSOCIATED KMO GENETIC VARIATION
C. Lavebratt*(1), S. Olsson(1), L. Backlund(1), U. Ösby(1), L.
Frisén(1), M. Landén(1,2), S. Erhardt(1), G. Engberg(1), M.
Schalling(1)
1. Karolinska Institutet 2. The Sahlgrenska Academy at Gothenburg
University
*catharina.lavebratt@ki.se
Introduction: Cognitive impairments of executive function, attention
and memory are present in bipolar disorder.Kynurenic acid (KYNA)
influences brain glutamatergic and cholinergic transmission by
antagonizing the NMDA receptorand the a7 nicotinic acetylcholine
receptor. In addition, elevated levels of endogenous KYNA increases
brain dopamine firing. The concentration of KYNA in CSF was
previously reported to be elevated in bipolar disorder. KYNA is one
of three products of three different enzymatic modifications of Lkynurenine.
The enzymes producing KYNA are kynurenine
aminotransferases (KATs). Kynurenine 3-monooxygenase (KMO),
which forms 3-hydroxykynurenine, is rate limiting in the metabolism
of KYNA since it is the enzyme being most specific and with the
highest affinity for kynurenine. Reduced KMO activity will thus
shunt the synthesis towards KYNA. The purpose of this study was to
elucidate if genetic variation in KMO contributes to the elevated
KYNA level observed in CSF of bipolar disorder type 1 patients.
Methodology: KYNA levels were measured in CSF from 99
Swedish bipolar disorder patients. SNPs covering 79% of the
variation in KMO were genotyped in these patients and in a second
sample of 487 Swedish bipolar disorder type 1 patients and 1044
Swedish anonymous blood donors.
Results: We found that KYNA levels were elevated in CSF of
bipolar disorder patients with a history of psychotic episodes (n=48),
compared to non-psychotic bipolar disorder patients (P=0.039).
KYNA levels in CSF were higher in those psychotic bipolar patients
homozygous for the major C-allele of the KMO SNP rs1053230
(P=0.010, n=31). This link between psychotic bipolar patients and
homozygosity for the rs1053230 C-allele was supported by findings
in 487 bipolar type 1 patients where homozygosity of the C-allele
was more common among bipolar disorder type 1 patients with
history of psychosis (n= 344) compared to other bipolar disorder type
1 patients (OR=1.6, P=0.0093). Haplotype analysis further indicated
that haplotype carrying the rs1053230 C-allele was overrepresented
in psychotic bipolar type 1 patients compared to non-psychotic
bipolar patients (P=0.0096), and compared to healthy blood donors
(n=1044, P=0.030).KMO is located in the outer membrane of
mitochondria, primarily inside the membrane. The SNP rs1053230
lies at a putative site for substrate interaction outside of the
membrane and defines a variation between hydrophilic Arg and
hydrophobic Cys.
Conclusions: Variation in KMO leads to variation in KYNA, that
influences glutamatergic, cholinergic and dopaminergic transmission.
Variation in KMO provides a genetic marker of cognitive impairment
in bipolar disorder patients with psychosis.
130
PP122 COMMON POLYGENIC VARIATION
CONTRIBUTING TO SCHIZOPHRENIA RISK ALSO
EXPLAINS VARIATION IN TOTAL BRAIN VOLUME
ECIP
A. Terwisscha van Schel*(1), S. Bakker(1), N. van Haren(1), H.
Boos(1), W. Cahn(1), H. Hulshoff Pol(1), R. Ophoff(1,2), R. Kahn(1)
1. University Medical Centre Utrecht 2. University of California, Los
Angeles
*aterwiss@umcutrecht.nl
Introduction: Schizophrenia patients have, on average, 3% reduced
brain volumes on magnetic resonance imaging (MRI) scans. Brain
volume reductions in schizophrenia are associated with cognitive
decline and poor outcome. The factors underlying these volume
changes may therefore influence the core features of the disorder.
Moreover, brain volume reductions are highly heritable. The aim of
our study was to investigate if a large combined set of single
nucleotide polymorphisms (SNPs) associated with schizophrenia
explains brain volume, both in patients and controls.
Methodology: Subjects were genotyped using the Illumina
HumanHap550 beadchip. After quality control 122,462 SNPs were
used in the analysis. In the discovery sample (568 schizophrenia
patients and 511 controls) we performed a GWAS. We then defined
sets of SNPs with p-values below different thresholds (PT's). For each
individual in de target sample of 159 schizophrenia patients and 145
healthy controls we calculated the number of score alleles. Individual
polygenic schizophrenia scores (PSS) were calculated for every PT-
SNP set by weighting the number of score alleles by the logarithm of
the odds ratio from the GWAS (conform Purcell et al., 2009). We
measured total brain, gray matter, white matter, lateral and third
ventricle volume on a 1.5 Tesla MRI scan and corrected these for
age, sex and intracranial volume. We then performed linear
regressions using brain volumes as dependent variable and PSS as
independent variable. The analyses were repeated including also
disease status and disease*PSS interaction as independent variables.
Results: A higher PSS was significantly associated with reduced
total brain volume (TBV) at different PT's (e.g., for PT 0.3: R 2 =
0.036, p = 0.009) in the total sample. Similar effects of PSS were
seen on all other brain volume measures, with the largest effect on
third ventricle volume (R 2 = 0.066, p = 0.002). There was no
significant effect of PSS on disease status. The association is also
significant in the patient group only, but not in the control group
only.
Conclusions: This is the first study to show the genetic overlap
between schizophrenia and brain volume based on genotyping data,
suggesting shared biological pathways. Studying the biological
mechanisms of the aberrant brain structure in schizophrenia patients
might therefore culminate in important insights in disease
mechanisms. Finally, this study underlines the possible advantages of
using highly heritable, quantitative phenotypes, such as brain volume,
in genetic studies of complex disorders.

PP123 PRELIMINARY EVIDENCE OF GENE X
ENVIRONMENT INTERACTION BETWEEN 5HTTLPR
POLYMORPHISM AND PUBERTAL STATUS IN
ADOLESCENTS’ DEPRESSIVE SYMPTOMS: UNCOVERING
THE ROLE OF GENES IN SENSITIVE PERIODS OF
DEVELOPMENT
G. Salum*(1,2,4,6), A. Bortoluzzi(6,7), P. Silveira(1,3), V.
Bosa(1,3), I. Schuch(1,3), M. Goldani(3), C. Blaya(5,6), S. Leistner-
Segal(1), G. Manfro(1,2,4,6)
1. Federal University of Rio Grande do Sul 2. Post-Graduate Program
in Medical Sicences: Psychiatry 3. Center for Child and Adolescent
Health Studies (NESCA) 4. National Institute of Developmental
Psychiatry for Children and Adolescents (CNPq, Brazil) 5. Health
Sciences Federal University of Porto Alegre 6. Anxiety disorders
program for Child and Adolescent Psychiatry (PROTAIA) 7. Postgraduate
Program in Neuroscience. Health Basic Sciences Institute of
(ICBS)
*gsalumjr@gmail.com
Introduction: Puberty is a critical sensitive period associated with
the onset of several clinical phenotypes of psychiatric disorders. The
5HTTLPR polymorphism, with the embedded functional Single
Nucleotide Polymorphism (SNP), is consistently implicated as a
moderator of the effects of psychosocial stressors in psychiatric
disorders. The aim of this study is to investigate if puberty can be
experienced differently regarding depressive symptomatology
between those with high and low functional copies of 5HTTLPR.
Methodology: A total of 86 adolescents participated in a crosssectional
study including pre-pubertal, pubertal and post-pubertal
adolescents measured through Tanner stages. Depressive
symptomatology was assessed using self-rated the Childhood
Depressive Inventory (CDI). The 5HTTLPR was analyzed into three
groups classified in accordance with expression: LaLa vs. (LgLa or
LaS) vs. (LgLg or LgS or SS). We constructed a Generalized Linear
Model using depressive scores as dependent variable, 5HTTLPR and
Tanner stages as independent variables, as well as their interaction
term using robust estimators. In addition we controlled the analysis
for possible confounding factors as: age, gender, body fat, physical
inactivity. Interaction terms of the model were interpreted using
pairwise contrasts.
Results: We found a significant gene x environment interaction
between pubertal status and 5HTTLPR (p interaction=0.001). No
main effects were found for 5HTTLPR or Tanner stages itself.
Pairwise contrasts of CDI estimated marginal means between groups
reveal a dose-response gene x environment interaction. In those with
two copies of the high function allele (LaLa) there is an important
decrease in depressive symptoms after puberty - pre-pubertal 8.09
(SE=1.58), pubertal 9.51 (SE=2.06), post pubertal 1.84 (SE=0.91). In
those with one low functional copy (LgLa, LgS) this decrease is
attenuated - 8.80 (SE=2.31), 7.99 (SE=0.65), 6.10 (SE=0.95) and
there is no decrease in those with two copies of the functional allele
10.43 (SE=10.43), 8.71 (SE=2.05), 9.34 (SE=1.01).
Conclusions: Our findings suggest that 5HTTLPR has a major role
mediating persistence of depressive symptoms after puberty. Further
prospective studies should investigate this preliminary hypothesis.
131
PP124 COMMON AND DIFFERENT GENETIC
BACKGROUND WITHIN MAOA GENE FOR BOTH
SCHIZOPHRENIA AND MAJOR DEPRESSION DISORDER:
A CIS-PHASE INTERACTION STUDY
Q. Xu*, J. Zhang, Y. Chen, Y. Shen
Institute of Basic Medical Sciences, Chinese Academy of Medical
Sciences
*xuqi@pumc.edu.cn
Introduction: The genetic basis of schizophrenia and major
depression has been explored extensively, but a causal relationship
has been difficult to identify. We aimed to examine the effect of
multiple variants within MAOA gene on the pathogenesis of these
psychiatric disorders.
Methodology: We genotypedMAOA VNTR polymorphism and 19
SNPs within this gene in 512 unrelated major depression patients,
555 patients with paranoid SCZ and 567 controls from a Chinese
population. We explored the VNTR-SNP additive and cis-phase
interaction effect on the development of these two diseases. The
expression level of MAOA gene was also determined between
patients and controls by RT-PCR assays.
Results: The main findings of present study were that the MAOA
VNTR and functional SNPs may confer disease susceptibility to both
paranoid SCZ and MDD in the Chinese Han population through
different genetic interaction mechanism. In paranoid SCZ, MAOA
may act via multiple variant interactions (corrected P=0.021 in
female) whereas in MDD VNTR-L may act through the cisregulation
to inhibit gene expression (corrected P=0.017 in male).
Moreover, genetic variants within this gene could modify disease
susceptibility by altering gene expression (P=5.86E-07 in SCZ and
P=5.69E-05 in MDD). Also, genders can modify the genetic effect of
MAOAvariant in both disease
Conclusions: Our study provides useful information that multiple
variants interaction within MAOA gene plays an important role in the
pathogenesis of severe mental disorder and which may lead to better
understand of complex disorders genetic entities and aid genetic
analysis of most complex diseases at a deeper level.

PP125 ASSOCIATION STUDY OF GENETIC VARIATIONS
IN THE HUMAN MELATONIN RECEPTOR (MTNR1A AND
MTNR1B) GENES WITH MOOD DISORDERS AND
CHRONOBIOLOGICAL RELATED PHENOTYPES
V. Soria(1), M. Gratacòs *(2), V. Gálvez(1), G. Escaramís (2), J.
Crespo (1,3), J. Valero (4), A. Gutiérrez-Zotes (4), L. Martorell (4),
E. Vilella (4), J. Menchón(1,3),. Estivill (2,5), M. Urretavizcaya(1,3)
1. Department of Psychiatry, Bellvitge University Hospital, IDIBELL
2. Center for Genomic Regulation (CRG-UPF), CIBERESP (CIBER
en Epidemiología y Salud Pública) 3. Department of Clinical
Sciences, Bellvitge Campus, Barcelona University, CIBERSAM
(CIBER en Salud Mental) 4. Hospital Psiquiàtric Universitari Institut
Pere Mata, IISPV, Rovira i Virgili University 5. Experimental and
Health Sciences Department, Pompeu Fabra University
*monica.gratacos@crg.cat
Introduction: A large body of literature suggests that circadian
dysfunction plays an important role in the pathophysiology of mood
disorders (MD). Among the clinical hallmarks of MD are
disturbances in sleep/wake cycle, diurnal mood variation and a
seasonal pattern of symptom recurrence and remission. In fact,
disruptions of circadianrhythms, including abnormalities of circadian
phase position and in circadian oscillations of melatonin levels have
been described in both unipolar major depressive disorder (MDD)
and bipolar disorder (BD). Melatonin is a pineal gland hormone
involved in the synchronization of the circadian clock which signals
day-night information to the endogenous circadian pacemaker located
in the suprachiasmatic nucleus of the hypothalamus.
Methodology: We hypothesized that genetic variation in the
melatonin receptor genes could be associated to MD phenotypes. To
test this hypothesis we performed a case-control study including 440
screened control subjects and 445 unrelated patients with MD (256
MDD and 189 BD) diagnosed according to DSM-IV criteria. Patients
completed the Spanish versions of the Seasonal Pattern Assessment
Questionnaire and the Horne-Östberg Morningness-Eveningness
Questionnaire in order to evaluate chronobiological phenotypes
which presumably have a strong inherited component, such as
seasonality and diurnal preference or chronotype. First we selected a
set of TagSNPs representative of the common variation patterns
identified in the European population in the genomic region
containing the human melatonin receptors' genes (MTNR1A,
MTNR1B). We successfully genotyped 12 SNPs using the SNPlex
Genotyping System. Genetic association under four different models
of inheritance adjusted for covariates of interest were analyzed using
the statistical software environment R and the SNPassoc package.
Results: We found significant differences in genotype distributions
between MD cases and controls for 3 SNPs located in MTNR1B gene
(OR=1.72, P unc= 0.003 OR=1.41, Punc= 0.036 OR=1.42, Punc= 0.034).
In addition, a MTNR1B intronic variant was nominally associated
with Global Seasonality Scores (P=0.01) and a SNP located in the 5'
near region of MTNR1A gene was associated with diurnal preference
in MD patients (P=0.003).
Conclusions: These preliminary data suggest that the genetic
variability in MTNR1B gene could be involved in the susceptibility to
mood disorders. Further studies in larger samples are needed to
confirm that genetic variants in the melatonin receptor genes might
be a contributing factor to the susceptibility to MD and their
association with chronobiological related phenotypes.
132
PP126 GENOME-WIDE SIGNIFICANT RISK VARIANTS
FOR PSYCHOSIS AND NEURAL INTERMEDIATE
PHENOTYPES
A. Meyer-Lindenberg*
Central Institute of Mental Health
*a.meyer-lindenberg@zi-mannheim.de
Introduction: While GWAS will probably not provide all answers
about the genetics of schizophrenia, any common variant that does
survive the extreme amount of statistical thresholding that this
method requires certainly merits study using intermediate imaging
phenotypes. Of those variants, the one with the strongest support is
zinc finger protein 804A (ZNF804A) encoding a zinc-finger protein
of unknown, but possibly regulatory function. Like many candidate
gene variants, ZNF804A is pleiotropic on the level of psychiatric
diagnoses, also being associated with bipolar disorder.
Methodology: We use an imaging genetics approach in a sample of
n=110 Germans of German descent genotyped for ZNF804A risk
SNPs and studied using functional neuroimaging,
Results: In functional neuroimaging with an n-back working memory
probe, healthy carriers of risk genotypes exhibit no changes in
regional activity. However, they did exhibit pronounced gene dosagedependent
alterations in functional connectivity, which was decreased
from DLPFC across hemispheres and increased with
hippocampus, similar to findings in patients. These connectivity
abnormalities were specific to working memory. Subsequent
workshowed an inability to downregulate key parts of the
mentalizing system in conjunction with impaired connectivity of this
system to DLPFC, suggesting possible downstream functional
activation effects of impaired prefrontal connectivity that mirror
findings in patients. Interestingly, abnormally increased coupling of
amygdala was also observed, a phenotype unlikely to be related to
heritable risk for schizophrenia and therefore possibly related to risk
for bipolar disorder, where similar findings in patients have been
described.
Conclusions: Neural intermediate phenotypes related to risk for
schizophrenia and bipolar disorder through Z NF804A genetic risk
variants can be defined and map onto systems previously implicated
in patients.

PP127 RISK FACTORS FOR SUICIDE ATTEMPTS IN
PATIENTS WITH BIPOLAR DISORDER
Y. Ahn *(1,2,3), J. Song(1,2), H. Yu(2), Y. Kim (1,2,3)
1. Department of Psychiatry and Behavioral Science, Seoul National
University College of Medicine 2. Department of Neuropsychiatry,
Seoul National University Hospital 3. Institute of Human Behavioral
Medicine, Seoul National University College of Medicine
*aym@snu.ac.kr
Introduction: Suicide is one of the greatest burdens among patients
with psychiatric disorders. According to many studies, bipolar
disorder is one of the most consistent risk factors for suicide. This
study compared the characteristics of bipolar disorder patients with
and without a history of suicide attempts to identify the risk factors
for suicide in this disorder.
Methodology: Two hundred twelve patients with bipolar disorder
were recruited from the Bipolar Disorder Clinic at the Department of
Neuropsychiatry, Seoul National University Hospital. The patients
participated in the genetic study and were individually interviewed
with the Diagnostic Interview for Genetic Studies (DIGS). We
compared the demographic and clinical characteristics of those
participants who did and did not attempt suicide.
Results: Forty-four (21.2%) patients had histories of suicide
attempts. Suicide attempters were younger, more likely to be
diagnosed with bipolar II disorder. The variables that differentiated
those who did from those who did not attempt suicide included age at
first contact, lifetime history of antidepressant use, major depressive
episode, mixed episode, auditory hallucinations, rapid cycling, the
number of previous mood episodes, age of first depressive episode,
and age of first psychotic symptoms. Strong predictors for suicide
attempts were younger age at onset, lifetime history of auditory
hallucinations, and history of antidepressant use. Discrete-time
survival analysis revealed that antecedent depressive episodes and
psychotic symptoms predicted the first suicide attempt in patients
with bipolar disorder.
Conclusions: Bipolar disorder is one of the major psychiatric
conditions associated with the high lifetime risk for suicide. Thus, it
is important that clinicians understand the major risk factors for
suicidal behavior so that they can develop and implement improved
strategies for dealing with this complex behavior.
133
PP128 EVIDENCE OF AN ASSOCIATION BETWEEN
DYSBINDIN GENE AND AGE AT ONSET IN
SCHIZOPHRENIA
K. Lee*(1), E. Joo(1), Y. Kim(2)
1. Department of Neuropsychiatry, Eulji University School of
Medicine, Eulji General Hospital 2. Department of Psychiatry &
Behavioral Science and Institute of Human Behavioral Medicine,
Seoul National University College of Medicine
*lky@eulji.ac.kr
Introduction: The dysbindin gene (DTNBP1) is located in
chromosome 6p22.3, one of the regions of positive linkage for
schizophrenia. In particular, dysbindin protein has been found to play
a role in the glutatmate neural transmission in the brain. A strong
genetic association between DTNBP1 and schizophrenia has been
replicated through many recent studies. However, we have not
replicated positive association between DTNBP1 and schizophrenia
in our Korean sample. Because schizophrenia has been regarded as a
disease with a quite heterogeneous origin and evolvement, it is useful
to categorize patients with schizophrenia into relatively homogeneous
subsets based on clinical characteristics including age at onset
(AAO). Therefore, we investigated the association between DTNBP1
and AAOof schizophrenia.
Methodology: We assessed age at first occurrence of positive
psychotic symptomsof 197 patients with schizophrenia. Three SNPs,
SNPA, P1763, P1320 of DTNBP1were genotyped.
Results: In SNPA, patients with AT (N=10) showed significant
earlier AAO than those with AA (N=187) (p

PP129 A CANDIDATE GENE STUDY OF CHILD ANXIETY
DISORDERS AND RESPONSE TO COGNITIVE BEHAVIOR
THERAPY
ECIP
K. Lester*(1), J. Hudson(2), C. Creswell(3), M. Tropeano(1), P.
Cooper(3), A. Farmer(1), C. Lewis(1), H. Lyneham(2), R. Rapee(2),
D. Collier(1), T. Eley(1)
1. King's College London, MRC Social, Genetic and Developmental
Psychiatry Centre, Institute of Psychiatry 2. Centre for Emotional
Health, Department of Psychology, Macquarie University 3.
Winnicott Research Unit, School of Psychology and Clinical
Languages Sciences, University of Reading
*kathryn.lester@kcl.ac.uk
Introduction: Anxiety disorders are highly prevalent and debilitating
conditions that frequently emerge during childhood. Childhood
anxiety is associated with a wide range of impairments and often
precedes other major psychological and physical problems. Like most
complex traits, anxiety disorders are under genetic influence, but
little is known about specific genes involved. Given the pervasive
negative effects of anxiety on children's development, it is important
to not only understand the factors involved in the onset and
maintenance of child anxiety but it is also of critical importance to
treat child anxiety disorders successfully. Cognitive-behavior therapy
(CBT) is the treatment of choice for child anxiety disorders, and is
effective in around 60% of cases. Poor treatment prognosis is
associated with increased symptom severity, parental
psychopathology and comorbid mood disorders, all of which could
reflect genetic influence. The role of specific genetic markers in
predicting response to psychological therapy has received almost no
attention to date. However, our group has recently shown that the
5HTTLPR moderates CBT treatment response.
Methodology: 467 anxiety-disordered children aged 6 to 13 years
(with 4 grandparents of white European ancestry) undergoing
manualised CBT were recruited from Reading, UK and Sydney,
Australia. DNA was extracted from buccal-cells. A comparison
control sample comprised 459 never psychiatrically-ill white
Europeans. CBT response was defined using parent and child
structured diagnostic interviews and clinician severity ratings for
primary and all anxiety disorders. Genotyping was performed for
markers in selected candidate genes previously associated with
relevant phenotypes: Glucocorticoid Receptor (GR) Corticotrophin
Releasing Hormone (CRH) Regulator of G Protein Signalling 2
(RGS2) Glutamic Acid Decarboxylase (GAD) and Nerve Growth
Factor (NGF).
Results: Case-control differences were significant for GR bcl1 (X²(1)
= 4.40, p = .04) RGS2 rs10801152 (X²(2) = 7.73, p = .02), RGS2
rs6428136 X²(2) = 6.42, p = .04) and GAD rs2241165 (X²(2) =
10.23, p = .006) but not CRH. An association was also observed
between NGF rs6330 and treatment response at follow-up. Positive
response at follow-up was seen in 17% and 13.2% more children with
the TT than CT/TT genotype for primary (X²(1) = 5.81, p = .02) and
all (X²(2) = 3.26, p = .07) anxiety disorder response respectively.
Conclusions: These findings support the notion that variants of the
GR, RGS2 and GAD gene may play a role in the etiology of
childhood anxiety disorders and that variants of the NGF gene may
contribute to the variability of response to psychological therapy.
Identifying factors that help detect children at risk for developing
anxiety disorders could lead to prevention programmes targeting
vulnerable children during periods of high stress. Knowledge of
genetic factors could also be used to inform treatment choices with
respect to psychotherapeutic interventions.
134
PP130 ASSOCIATION BETWEEN COPY NUMBER
VARIATION OF GLYCOGEN SYNTHASE KINASE 3 BETA
AND MOOD DISORDER
Z. Elek*, E. Szántai, R. Kovács-Nagy, G. Faludi, Z. Rónai, M.
Sasvári-Székely
SE
*el.zsuzsa@gmail.com
Introduction: Investigation of copy number variations (CNV) is a
novel approach in candidate gene studies. CNVs are caused by the
gain or loss of genetic material of 150–500 kb length, these
polymorphisms have been shown to be the significant source of
genetic variation between humans. Recently, glycogen synthase
kinase 3 beta (Gsk3beta) and the adjacent gene, Nr1i2 (pregnane X
receptor isoform) have been reported to associate with bipolar
depression.
Methodology: Here we present a case-control study of 221 patients
with mood disorder and 180 controls, involving the chromosomal
region of glycogen synthase kinase 3 beta (Gsk3beta) and the
flanking genes, Nr1i2 and C3orf15. Gene dosages have been
measured by real time PCR, analyses were confirmed by
conventional PCR and subsequent capillary electrophoresis.
Results: In accordance with previously published results, an
accumulation of increased copy number has been found in the patient
group (5/221 vs. 1/180). Simultaneous analysis of our results and
those published by Lachman et al. (1) suggests that the amplification
of this region is in association with mood disorder (p = 0.006). We
extended our study to analyze the expansion of the region affected by
the CNV, and demonstrated the altered copy number of exon 9 of
Nr1i2 and exons 5 as well as 9 of Gsk3beta regions, however neither
the Gsk3beta, nor the Nr1i2 promoters were involved in the CNV
region. Consequently, the increased gene dosage measured in the
Gsk3beta coding region does not include necessarily the complete
functional unit of the gene.
Conclusions: In conclusion our study confirmed that CNVs are
important components of the genetic background of complex
psychiatric disorders, identification of their accurate molecular
biological role requires however further analyses.

PP131 COGNITIVE SYMPTOMS IN MANIA ASSOCIATED
WITH THE DAOA AND COMT GENES
D. Hukic*, C. Lavebratt, L. Frisén, L. Backlund, M. Schalling, U.
Ösby
Karolinska Institutet
*dzana8@hotmail.com
Introduction: Manic symptoms are pathognomonic in bipolar
disorder. Individual symptoms of mania can be difficult to distinguish
but previous factor analyses have identified cognitive symptoms as a
valid group of manic symptoms. Combinations of manic symptoms
identified by factor analyses have until now not been used as
phenotypes in genetic analyses. The aim of this study was to
investigate genetic associations between cognitive symptoms in
bipolar mania grouped by factor analyses, and SNPs in the candidate
genes DAOA and COMT, in case-case and case-control analysis.
Methodology: Bipolar type 1 patients (n=631) from Sweden were
phenotyped focusing on the most severe episode of mania. A factor
analysis showed that the symptoms of pressured speech - disturbed
concentration - racing thoughts, formed a factor of cognitive
dysfunction (n=291; 46%). DNA was extracted from venous blood,
and 78 SNPs were selected. 1,044 anonymous blood donors served as
controls (ABD controls). The TaqMan OpenArray system (Applied
Biosystems) was used for genotyping and allelic discrimination was
analyzed with the TaqMan Genotyper Software (Applied
Biosystems).
Results: In the case-case analysis of DAOA, SNPs rs3916967 (P=
0.014) and rs2391191 (P =0.040), C respectively A allele were both
significantly associated with the non-cognitive dysfunction patients.
Also, they formed a protective haplotype CA (OR=0.77, P=0.067),
and a risk haplotype TG (OR =1.29, P =0.080). In the case-control
analysis of DAOA, rs3916967 (P =0.035) and rs239119 (P =0.028),
C respectively A allele were both significantly associated with noncognitive
dysfunction patients compared to controls. Haplotype
analysis showed a protective haplotype (CA, OR= 0.82, P =0.088),
and a risk haplotype (TG, OR =1.22, P =0.090). In the case-case
analysis of COMT, SNP rs5993883 (P=0.024), T allele was
significantly associated with non-cognitive dysfunction patients,
while SNP rs165599 (P=0.036), G allele was associated with
cognitive dysfunction. In the case-control analysis of COMT, both
SNPs rs5993883 (P=0.0037) and rs165599 (P=0.018), G allele for
both SNPs were associated with cognitive dysfunction.
Conclusions: We found genetic associations between cognitive
function/dysfunction and the DAOA and COMT genes, both in casecase
and case-control analyses. The result is in line with earlier
findings of the DAOA (D-amino acid oxidase activator) gene
complex as one of the most interesting loci for the major psychiatric
disorders. DAOA is a part of central glutamate system and plays an
essential role in the formation of memory and neuronal development.
The association of DAOA with schizophrenia has led to the
development of several potential treatment agents, active in animal
models that produce antipsychotic effects by enhancing NMDA
receptor function. The DAOA gene is located in a region with a
positive linkage peak for bipolar disorder. DAOA is an activator of
the DAO protein, involved in the metabolismof D-serine, which plays
a role in glutamatergic neurotransmission. Glutamate signaling is
involved in brain development and synaptic plasticity, both of which
are modified in individuals affected with bipolar disorder.The COMT
gene has been analyzed in several psychiatric disorders because of its
effect on cognitive and emotional function. In the last few years a
number of studies have investigated the association between COMT
polymorphisms and both suicidal behavior and personality traits.
135
PP132 EMOTIONAL MODULATION OF RESPONSE
INHIBITION IN UNAFFECTED SIBLINGS OF PATIENTS
WITH BIPOLAR I DISORDER
J. Brand(1), T. Goldberg(1,2,3), C. Gopin(1), A. Malhotra(1,2,3), K.
Burdick*(1,2,3)
1. Zucker Hillside Hospital-NSLIJHS 2. The Feinstein Institute for
Medical Research 3. Albert Einstein College of Medicine
*kburdick@nshs.edu
Introduction: Bipolar disorder (BPD) research has identified a
number of neurocognitive deficits as potential vulnerability markers
of the disorder however, very few studies have focused on patterns of
performance on affective processing tasks (e.g. Affective Go/No-Go
tasks) which may be more closely tied to the pathophysiology of the
illness than standard neuropsychological measures. We have
previously demonstrated that stable BPD patients demonstrate a more
liberal response bias to negative affective stimuli than healthy
controls or patients with schizophrenia (Gopin et al., 2011). The
purpose of the current study was to expand upon these prior findings
and investigate these patterns in the unaffected siblings of patients
with BPD and to compare them with healthy volunteers who do not
have a first degree relative with psychiatric illness.
Methodology: An affective Go/No-Go test was used to evaluate
inhibitory response to negatively-valenced, positively-valenced, and
neutral stimuli in unaffected siblings (n=20) and healthy controls
(n=20). Accuracy (d') and response bias (beta) served as dependent
variables in a series of repeated measures ANCOVAs and
independent samples ANOVAs.
Results: We found a non-significant main effect for group when
comparing accuracy performance (d') on the Affective Go/No-Go of
unaffected siblings vs. unrelated healthy controls [F = .984 (2, 34), p
= .384]. However, very similar to the pattern that we previously
reported in stable BPD patients, unaffected siblings showed a more
liberal response bias (beta) toward negatively valenced stimuli in
comparison with healthy controls [Main effect of group: F = 3.97 (2,
34), p = .028].
Conclusions: The current results extend our recent work which
suggested that bipolar patients – as opposed to individuals with
schizophrenia and healthy controls – are more willing to respond to
negative target stimuli (Gopin et al, 2011). These new data,
indicating that unaffected siblings demonstrate an affective
processing bias similar to that seen in the patient group, implicate this
task as a potential endophenotype in bipolar disorder.

PP133 LINKAGE AND ASSOCIATION ANALYSIS OF THE
WFS1GENE
N. Németh*(1), Z. Bognár(1), Z. Elek(1), G. Varga(2), A. Veres-
Székely(2), Z. Rónai(1), M. Sasvári-Székely(2)
1. Semmelweis University 2. Eötvös Lorand University
*nora.nemeth@eok.sote.hu
Introduction: WFS1 codes the wolframin, which is located in the
membrane of the endoplasmic reticulum. Loss-of-function mutations
of this gene are responsible for the Wolfram-syndrome, often
associated with psychiatric symptoms. Our earlier results showed that
the rare allele of the rs1046322 SNP was more frequent in the group
of people with a depression (tendency). Here we examined several
SNPs of the WFS1 gene to assess linkage disequilibrium in this
region. An association study was also carried out, to investigate the
connection between the WFS1 and the impulsivity endophenotype.
Methodology: PCR based techniques were employed for the
genotype analysis of rs1046322 SNP. Impulsivity was measured by
the Barratt Impulsivity Scale. Genotype-phenotype association was
analyzed by ANOVA. Further genotyping for the linkage study was
done by OpenArray real-time PCR Platform. Linkage analysis was
carried out by the GOLD software package.
Results: From 680 healthy persons, participants possessing the
rs1046322 A allele, obtained a significant higher score at the Barratt
Impulsivity Scale (p=0,009). In our pilot study the linkage between
the 3 SNPs was determined. Our findings suggested that there was
only a moderate linkage between rs1046322 and rs1046320 SNPs
(D`=0,282) as well as between rs1046322 and rs9457 polymorphisms
(D`=0,302). In contrast, a strong linkage (D`=0,959) was
demonstrated between the rs1046320 and the rs9457 variations.
Conclusions: Our results confirmed the assumption that the
polymorphic variants of the WFS1 gene could contribute to the
genetic background of psychiatric diseases. Earlier researches
showed the strongest association between diabetes mellitus and the
rs1046320 SNP, but a functional effect of this polymorphism has not
yet been proved. Considering our results the biological role of the
rs9457 SNP is possible, as it is not only linked to the rs1046320 SNP,
but it was also suggested that the SNP influences the binding site of a
miRNA, which can be the background of the biological effect.
136
PP134 SCHIZOPHRENIA GWAS FOLLOW-UP
IMPLICATES THE MHC REGION IN COGNITION
J. Walters*(1), G. Donohoe(2), G. Russo(1), S. Dwyer(1), H.
Williams(1), A. Corvin(2), G. Michael(2), I. Giegling(3), D.
Rujescu(3), M. O'Donovan(1), M. Owen (1)
1. Neuroscience and Mental Health Research Institute, MRC Centre
for Neuropsychiatric Genetics and Genomics, Cardiff University 2.
Neuropsychiatric Genetics Research Group, Department of
Psychiatry and Institute of Molecular Medicine, Trinity College 3.
Molecular and Clinical Neurobiology and Department of Psychiatry,
Ludwig- Maximilians-University
*waltersjt@cardiff.ac.uk
Introduction: Genome-wide association studies (GWAS) have
begun to successfully identify novel genetic risk variants and
associated biological pathways in schizophrenia. Three companion
studies recently reported the first genome-wide significant risk
variants for schizophrenia and additional GWAS significant
schizophrenia risk alleles have been discovered by the Psychiatric
GWAS Consortium. To take these results forward the actions of such
polymorphisms need to be identified, be that at the level of protein,
cell, neural circuit or phenotype. Neurocognition offers a way of
exploring the action of polymorphisms on behavioural neural circuits
and has the potential to prioritise risk variants that influence
cognition in schizophrenia- a key therapeutic target. In this study we
set out to investigate the influence of the genome-wide significant
risk variants on cognitive phenotypes in schizophrenia cases and
healthy controls.
Methodology: In a discovery and replication phase we used two
large large independent European Caucasian samples of healthy
controls (totalling n=2500) and cases with DSM-IV schizophrenia
(n=700). Participants in both the discovery and replication samples
underwent comprehensive neurocognitive assessment using
recognised cognitive batteries. A limited number of tests were
selected a priori to be equivalent in the two samples and to represent
domains of cognition known to be compromised in schizophrenia IQ,
episodic memory, working memory and attention.
With the aim of limiting multiple testing a representative panel of
SNPs was selected to provide coverage for all genome-wide
significant Sz signals thus far identified. Using linear regression we
analyzed associations with cognition for this panel of SNPs.
Results: The majority of SNPs that are genome-wide significant for
schizophrenia do not demonstrate association with cognition in this
adequately powered design (p>0.05). The MHC region is associated
with cognition such that the risk alleles for schizophrenia are
associated with diminished cognitive funciton (range of significant p
values for cognitive tests, p=0.001-0.004). These results replicate in
the same allelic direction in an independent sample (p=0.015).
Conclusions: Recent evidence suggests there is at most limited
overlap between the genetics of schizophrenia and cognition. Our
results are consistent with these findings in that the majority of
genome-wide significant SNPs in schizophrenia do not appear to be
associated with perforamnce across a range of cognitive domains.
However SNPs in the MHC region displayed robust association with
cognition, a result that was independently replicated. Whilst the
MHC region is genetically complex, further investigation is
warranted given its apparent dual role in schizophrenia and cognition
and the rich potential to identify novel treatment pathways, which
may include the newly discovered role for the MHC complex in
synaptic development and plasticity.

PP135 BURNOUT CLUSTERS AND SLEEP SYMPTOMS
S. Sulkava(1), S. Schoenauer(2), H. Mannila(3), T. Paunio*(1)
1. National Institute for Health and Welfare 2. University of Helsinki
and Helsinki Institute for Information Technology 3. Aalto
University
*tiina.paunio@thl.fi
Introduction: Burnout is a work-related stress syndrome that is
linked to sleep disturbances. The most common measure for burnout
is the Maslach Burnout Inventory (MBI) which covers three
dimensions of burnout syndrome: emotional exhaustion (EX),
cynicism (CY) and reduced professional self-esteem (PROF). In this
study we explored if naturally occurring MBI clusters correlate with
different aspects of sleep.
Methodology: Our Finnish population-based study sample consisted
of 3224 workers with information on MBI, sleep length, early
morning awakenings, fatigue and Global Seasonality Score. We
performed clustering analysis for 16 items of MBI using k-means
algorithm separately for males and females. The stability of the
results was ensured. Correlations of clusters and sleep traits were
analysed. Data comprising 550 000 genome-wide distributed single
nucleotide polymorphisms (SNPs) from ~1460 subjects will be
correlated with the obtained cluster solutions.
Results: We found analogous stable 4 cluster solutions for both
sexes. The biggest group ("C-Low ") consisted of individuals with
generally low scores. Individuals with symptoms of cynicism and
exhaustion were clustered together and formed two clusters based on
the degree of the symptoms ("C-Intermediate" and "C-High").
Individuals with problems of PROF constituted another cluster ("C-
Prof"). Correlations of sleep measures and MBI clusters were highly
significant. Sleep was the shortest and the most fragmented, and
complaints about fatigue were the most common in the cluster C-
High. Individuals in C-Prof had slightly elevated symptom scores
relative to those in C-Low, but lower than among those in C-
Intermediate.
Conclusions: Data mining of MBI show stable clusterings separating
individuals with different degrees of symptoms from the subscales
EX and CY from the individuals with the most prominent symptoms
from the subscale PROF. Individuals differ in sleep related traits
according to their cluster such that individuals in the C-high and Cintermediate
clusters exhibit most symptoms. Our results support the
view that altered sleep is an important aspect of burnout syndrome.
The study will comprise a template for subsequent molecular genetic
analyses.
137
PP136 GENOME-WIDE SUPPORTED RISK VARIANT FOR
SCHIZOPHRENIA IMPACTS ON HIPPOCAMPUS
ACTIVATION DURING CONTEXTUAL FEAR
CONDITIONING
S. Pohlack(1), V. Nieratschker*(2), F. Nees(1), M. Ruttorf(3), S.
Witt(2), M. Rietschel(2), H. Flor(1)
1. Department of Cognitive and Clinical Neuroscience,Central
Institute of Mental Health 2. Department of Genetic Epidemiology in
Psychiatry, Central Institute of Mental Health 3. Computer Assisted
Clinical Medicine, Medical Faculty Mannheim, Heidelberg
University
*vanessa.nieratschker@zi-mannheim.de
Introduction: Key features of schizophrenia are declarative memory
and contextual processing deficits. Recently, the neurogranin gene
has been linked to schizophrenia in a genome-wide association study.
Neurogranin is abundantly expressed in key regions of contextual
learning and discrimination, such as the hippocampus. Further,
abnormal functioning of the hippocampal formation as a major site
for cognitive and contextual processing has been found in
schizophrenia. Contextual fear conditioning is heritable (35-45%) and
constitutes a paradigm that is well suited to examine the impact of the
genome-wide supported variant rs12807809 on cognitive and
contextual processing.
Methodology: Hence, we employed an imaging genetics approach in
healthy volunteers to investigate the influence of rs12807809 on the
hippocampus during a contextual fear conditioning paradigm using
structural as well as functional magnetic resonance imaging (fMRI).
Results: Carriers of the schizophrenia risk-allele variant showed
significantly decreased activations in the left hippocampus during
acquisition, indicating impaired hippocampal activity during
contextual learning.
Conclusions: The present results suggest that contextual fear
conditioning might constitute a valuable endophenotype for
schizophrenia research. However, independent replication of our
results is necessary.

PP137 PHENOTYPIC CHARACTERIZATION OF
SCHIZOAFFECTIVE DISORDER-BIPOLAR TYPE: A
COMPARISON WITH BIPOLAR I DISORDER
L. Forty*(1), K. Gordon-Smith(1,2), E. Russell(1), L. Jones(2), I.
Jones(1), J. Walters(1), N. Craddock(1)
1. Cardiff University 2. University of Birmingham
*fortyl@cf.ac.uk
Introduction: The term schizoaffective disorder is used to describe
the co occurrence of symptoms suggesting both schizophrenia and
mood disorders. There have been various definitions of
schizoaffective disorder and the diagnostic category remains poorly
defined with boundaries between affective disorder, schizoaffective
disorder and schizophrenia remaining indistinct. We have shown
schizoaffective bipolar disorder [SABD] to be of particular genetic
interest and found that participants with RDC schizoaffective
disorder - bipolar type stand out genetically from both those
participants with bipolar disorder [BD] and those with schizophrenia
[SCZ]. Here we examine phenotypic differences between SABD and
BD.
Methodology: Diagnostic and clinical ratings, including the OPCRIT
symptom checklist, were undertaken on 1731 individuals collected as
part of ongoing molecular genetic studies of mood and psychotic
disorders. Narrow (DSM-IV) and broad (Research Diagnostic
Criteria) definitions of SABD were employed. For each of the
clinical variables being investigated, a separate logistic regression
analysis including specified covariates, was conducted to see if the
selected variable was predictive of SABD diagnosis.
Results: Including sex, age at interview, illness duration and method
of recruitment as covariates in each logistic regression analysis, the
following variables were predictive of a SABD, rather than a BD,
diagnosis: Earlier age at onset of illness and psychosis (p

PP139 WHITE-MATTER VOLUME AND GENETIC
ANALYSES OF THE MYELIN OLIGODENDROCYTE
GLYCOPROTEIN (MOG) AND OLIGODENDROCYTE
LINEAGE TRANSCRIPTION FACTOR 2 (OLIG2) GENES IN
PATIENTS WITH PEDIATRIC OBSESSIVE-COMPULSIVE
DISORDER (OCD)
G. Zai*(1,2), P. Arnold(2,3), M. Richter(1,2,4), G. Hanna(5), D.
Rosenberg(6), J. Kennedy(1,2)
1. Neurogenetics Section, Centre for Addiction and Mental Health 2.
Department of Psychiatry, University of Toronto 3. Program in
Genetics and Genomic Biology and Department of Psychiatry, The
Hospital for Sick Children 4. Department of Psychiatry, Sunnybrook
Health Science Centre 5. Department of Psychiatry, University of
Michigan 6. Department of Psychiatry, Wayne State University and
The Children's Hospital of Michigan
*gwyneth_zai@camh.net
Introduction: Several recent neuroimaging studies have implicated
abnormalities of white matter in patients with obsessive-compulsive
disorder (OCD). The myelination genes, myelin oligodendrocyte
glycoprotein (MOG) and oligodendrocyte lineage transcription factor
2 (OLIG2), have previously demonstrated significant association with
this disorder, and are clear candidates for white matter
alterations. The purpose of this study is to examine the relationship
between white matter volume in OCD and genetic variations in MOG
and OLIG2 genes.
Methodology: Two polymorphisms in the MOG gene,
MOG(C1334T) and MOG(C10991T), and a polymorphism in the
OLIG2 gene, rs928736, were investigated for association with total
white matter volume as measured using magnetic resonance imaging
(MRI) as well as left/right/total anterior cingulate gyrus and
left/right/total orbitofrontal cortex (OFC) white matter volumes in 37
pediatric OCD patients. We compared white matter volumes
between allele and genotype groups for each polymorphism using
Analysis of Covariance (ANCOVA).
Results: In our preliminary analysis, a significant relationship was
detected between genotype 2/2 of MOG(C10991T) and decreased
total white matter volume (P=0.016) and a trend was also observed
between genotype of MOG(C1334T) and white matter volume
(P=0.059). We did not observe significant evidence for association
for the other tested polymorphisms or white matter regions.
Conclusions: Our results showed a correlation between a MOG
genetic variant and white matter volume. This finding is intriguing in
light of the important role of white matter alteration in the
pathoetiology of at least some cases of childhood-onset
OCD. Further investigation with larger samples and sub-regional
white matter volume phenotypes is required.
139
PP140 ASSOCIATION STUDY BETWEEN EATING
DISORDER SUB-PHENOTYPES AND SEROTONINERGIC
GENES
B. Camarena*(1), S. Hernandez(1), L. Gonzalez(2), G. Flores(2), L.
Campos(1), V. Vazquez(2), A. Caballero(2)
1. Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Dept.
Genética. 2. Instituto Nacional de Psiquiatría Ramón de la Fuente,
Eating Disorders Clinic, Mexico City
*camare@imp.edu.mx
Introduction: Several lines of evidence implicate the serotoninergic
system in body weight regulation and more specifically in eating
disorders (ED). Interestingly, psychopathological traits that identify
clinical sub-phenotypes have been associated with a serotoninergic
dysfunction. In particular, a functional polymorphism located on the
promoter region of SLC6A4 gene (5-HTTLPR) has been associated
with impulsivity, novelty-seeking and compulsivity in ED. In
addition, the 5-HT1Dβ is involved in the regulation of 5-HT release
from serotoninergic neuron terminals in the brain. Therefore,
abnormal function of this auto-receptor could be involved in the
serotonin dysfunction suggested in ED. We examined association
between SLC6A4 and 5-HT1Dβ gene polymorphisms and clinical
sub-phenotypes in patients with bulimia and anorexia spectrum eating
disorders using a family-based method.
Methodology: Our sample consisted of 168 families, 119 patients
with bulimia-spectrum disorders (41% with BN purge type, 3% with
BN non-purge type, 8% with AN binge-eating/purging type, 19%
with bulimia-spectrum EDNOS) and 49 patients with anorexiaspectrum
disorders (15% with AN restricting type and 14% with
anorexia-spectrum EDNOS) according to DSM-IV criteria. Sample
was recruited from Eating Disorder Clinic of INPRFM in Mexico
City. Symptoms were evaluated using EDI scale, Plutchik´s
Impulsivity Scale, Overt Aggression Scale, YB-Cornell, HAM-A,
and HAM-D. DNA was analyzed by PCR and 5’exonuclease assay
using TaqMan allelic discrimination assays for SLC6A4
polymorphisms: 5HTTLPR, rs25531 and rs6355; and 5-HT1Dβ:
rs6296, rs6297 and rs130058. Significance level was adjusted to
p≤0.0083.
Results: FBAT analysis of SLC6A4 gene polymorphisms in bulimiaspectrum
families showed a high transmission of 5HTTLPR s allele
(z=2.94, p=0.0033). However, 5-HT1Dβ gene polymorphism did not
show linkage disequilibrium in anorexia-spectrum families
(p≥0.008). FBAT quantitative analysis of clinical sub-phenotypes in
bulimia-spectrum families of SLC6A4 gene polymorphism showed a
preferential transmission of 5HTTLPR s allele associated with high
scores of impulsivity (z=3.02, p=0.0025) and EDI-bulimia sub-scale
(z=3.6, p=0.00036), and a trend for significance for EDI-body
dissatisfaction sub-scale (z=2.6, p=0.0096). We did not find linkage
disequilibrium between 5-HT1Dβ gene and clinical sub-phenotypes
in bulimia-spectrum families. Finally, FBAT analysis in anorexiaspectrum
families did not show linkage disequilibrium between 5-
HT1Dβ gene polymorphisms and clinical sub-phenotypes.
Conclusions: We replicated the association between 5HTTLPR s
allele and bulimia-spectrum disorders. Also, we found association
between 5HTTLPR s allele and impulsivity in subjects with bulimiaspectrum
disorders. Therefore, our results support the findings that
link serotoninergic disturbances with trait of impulsivity or
dysregulation in bulimia patients. Analysis of alternative phenotypes
in larger samples is necessary to try to identify genetic variants
involves in ED subtypes.

PP141 GENOME-WIDE ANALYSES OF
NEUROCOGNITIVE/BRAINIMAGING PHENOTYPES
REVEAL ENRICHED ASSOCIATION OF NEURONAL AND
PSYCHIATRIC CANDIDATE GENES
ECIP
P. Lee*(1,2), A. Holmes(3,4), J. Fagerness(1), J. Roffman(3,4), S.
Purcell(1,2), R. Buckner(3,4), J. Smoller(1,2)
1. Department of Psychiatry, Harvard Medical School 2.
Neurodevelopmental & Psychiatric Genetics Unit, Center for Human
Genetics Research, Massachusetts General Hospital 3. Department of
Psychology, Center for Brain Science, Harvard University 4.
Athinoula A. Martinos Center for Biomedical Imaging,
Massachusetts General Hospital
*phlee@pngu.mgh.harvard.edu
Introduction: A number of recent neuroimaging genetics studies
have reported association of psychiatric risk genes with alterations in
the brain structure and function in apparently healthy subjects.
Notable examples include the functional effects of two schizophrenia
risk genes, ZNF804A and COMT on the disturbed regional
connectivity in the brain default networks. Nevertheless, most of
prior imaging genetics work used a candidate gene-based approach,
focusing on only a few, widely studied psychiatric candidate genes.
In this study, we employ an un-biased genome-wide analysis
(GWAS) of neurocognitive/brainimaging traits to elucidate genetic
influences on normal variation in brain structure and function, and
ultimately those underlying a psychiatric illness.
Methodology: Our study is based on the Brain Genomics Library
(BGL), a multi-site protocol for genetic studies of brain and
behavioral phenotypes. The BGL study enrolled more than 2,200
healthy volunteers in Boston, USA (average age 21.3; female ratio
55.96%). A group of 14 endophenotypes were assessed for all
participants, measuring diverse aspects of brain function, structure,
and personality/temperament relevant to major psychiatric illnesses.
Initial genotyping was done for 470 subjects of European ancestry,
yielding genotype data of 1,140,419 SNPs (Illumina OMNI 1M).
After quality control and imputation using the 1000 Genome Project
data, 5,888,968 SNPs with imputation quality scores of at least 0.8
were retained for statistical analysis. Logistic regression was
conducted on imputed allele dosages of individual SNPs for each of
14 phenotypes using age, sex, and four multidimensional scaling
(MDS) components as covariates. We also examined enriched
association of four brain-function and psychiatric candidate gene sets
using a GWAS-specific pathway analysis tool, INRICH
(http://atgu.mgh.harvard.edu/inrich).
Results: Single-SNP-based logistic regression found no SNPs with
genome wide significant association with any of 14 phenotypes.
Interesting findings were made in pathway analyses, which identified
enriched association of neuronal-activity genes with two functional
and structural brain-imaging phenotypes: Default Network
Connectivity (p=1.2e-03) and Left Amygdala Volume (p=1.3e-03).
Furthermore, two behavioral phenotypes of temperament and
personality, namely the Barratts scale and the Negative Affect
Composite score showed significant association with known
psychiatric candidate genes (p=2.3e-03 and 3.9e-04, respectively).
Conclusions: Using a GWAS analysis of
neurocognitive/brainimaging phenotypes, we found a potential role of
neuronal and psychiatric candidate genes in modulating the normal
variations of the brain structure, function, and
personality/temperament measures. It is noteworthy that a number of
recent pathway-based GWAS studies have reported involvement of
brain-function genes in the pathogenesis of schizophrenia, autism,
and bipolar disorder. Our work demonstrates that endophenotypebased
genetics studies of healthy subjects may provide a powerful
strategy for elucidating the neurogenetic risk mechanisms underlying
these psychiatric disorders, as well as for understanding the
functional consequences of specific genes involved in neuronal
activity.
140
PP142 BRAIN VOLUMETRIC PHENOTYPES AND
SEROTONIN SYSTEM GENETIC VARIATION IN
PEDIATRIC OBSESSIVE-COMPULSIVE DISORDER
P. Arnold*(1,2), V. Sinopoli(1,2), K. Wu(2), P. Easter(3), J.
Kennedy(2,4), G. Hanna(5), D. Rosenberg(3)
1. Hospital for Sick Children 2. University of Toronto 3. Wayne State
University and the Children's Hospital of Michigan 4. Centre for
Addiction and Mental Health 5. University of Michigan
*paul.arnold@sickkids.ca
Introduction: Serotonin system genes have been the most studied
candidate genes in OCD but evidence for association has been
equivocal. Individuals with OCD display regional volumetric brain
abnormalities, which provide promising intermediate phenotypes of
the disorder (Arnold et al., 2009). In this preliminary study we
examined the association between serotonergic system gene
polymorphisms and volumetric brain region abnormalities in children
with OCD.
Methodology: Volumes of brain regions selected for a priori
evidence of association with OCD (thalamus, anterior cingulate
cortex (ACC), orbitofrontal cortex (OFC), and caudate) were
measured using structural magnetic resonance imaging (sMRI) in 20
psychotropic-naïve pediatric OCD patients (ages 7 to 17). A total of
40 single nucleotide polymorphisms (SNPs) were analyzed from
three serotonergic candidate genes (serotonin transporter, SLC6A4;
serotonin receptor 2A, HTR2A; and serotonin receptor 1B, HTR1B)
for association with regional volume.
Results: In HTR2A, the C allele of single nucleotide polymorphism
(SNP), rs1923886, was found to be significantly associated with
reduction in volume of the left putamen (adjusted P-value of
0.035). The same SNP was nominally associated with total and right
putamen volume (not significant after adjustment for multiple
comparisons).
Conclusions: We identified an association between HTR2A and
volume of the putamen in psychotropic-naive children with OCD.
These results, although requiring replication in a larger sample
size, are consistent with previous neuroimaging findings implicating
the basal ganglia in OCD pathophysiology. Structural imaging
phenotypes provide potentially valuable intermediate phenotypes that
may be associated with decreased heterogeneity compared to
complex behaviours, and thereby facilitate the identification of risk
genes.

PP143 IMPACT OF CATECHOL-O-
METHYLTRANSFERASE VAL158MET (RS4680) GENOTYPE
ON VERBAL WORKING MEMORY IN WOMEN WITH HIV
E. Sundermann*(1), J. Bishop(2), L. Rubin(1), E. Martin(1), M.
Kreek(3), O. Levran(3), M. Randesi(3), K. Weber(4), M. Cohen(4),
M. Pauline(1)
1. University of Illinois at Chicago, Department of Psychiatry 2.
University of Illinois at Chicago, Department of Pharmacy Practice 3.
Rockefeller University, Laboratory of the Biology of Addictive
Diseases 4. The Core Center at Stroger Hospital of Cook County
*esundermann@psych.uic
Introduction: The HIV virus enters the central nervous system
(CNS) leading to neurological, cognitive and behavioral
complications. Even in the era of combination antiretroviral therapy,
mild neurocognitive impairment persists in approximately 33% of
HIV-infected individuals particularly in the domains of executive
function and learning and memory. The Val158Met (rs4680) single
nucleotide polymorphism (SNP) of the catechol-O-methyltransferase
gene (COMT) was shown to impact executive function through its
effect on dopamine metabolism in healthy individuals as well as
individuals with schizophrenia. HIV infection is associated with
decreased dopaminergic activity. Therefore, this study aims to
determine the effect of the Val158Met polymorphism on working
memory performance in women with HIV.
Methodology: Participants included 54 HIV seropositive women (33
Met allele carriers & 21 Val/Val) from the Chicago site of the
Women’s Interagency HIV Study. All participants were between the
ages of 25 and 64 (mean age = 43.6) and had no history of CNS
disease or major psychiatric disorders. The sample was 87% African
American (n=47). Participants completed the0, 1 and 2-back
conditions of the N-back test which is an established measure of
working memory. Hierarchical linear modeling was used to test the
association between the Val158Met SNP and N-back performance
after adjusting for relevant covariates.
Results: A significant effect of the Val158Met SNP was found on Nback
performance. Specifically, compared to women with the
Val/Val genotype, Met allele carriers had a significantly higher
percent correct on the 1-back (p

PP145 ESTABLISHMENT OF HOMOGENOUS SUB-GROUPS
IN ALZHEIMER’S DISEASE BY EVALUATING EPISTATIC
INTERACTIONS
S. Prabhu*(1), B. Bagepally(1), M. Varghese(2), M.
Purushottam(2), S. Jain(1,2), O. Mukherjee(1)
1. National Centre for Biological Sciences 2. National Institute of
Mental Health and Neurosciences
*sujanap@ncbs.res.in
Introduction: Alzheimer’s disease (AD) an irreversible and
progressive neurodegenerative disorder is the most common form of
dementia in the elderly. This disorder follows a dichotomous age
related model. The early onset form is less frequent and has less
number of risk genes associated with it having a higher penetrance.
The late onset AD is genetically heterogeneous and has been found to
have multiple gene of small effect interacting to give rise to the late
onset pathology. Linkage and candidate gene studies have previously
shown strong association of APOE (apoe 2/3/4) with dementia. The
COMT (Val158Met) enzyme catechol-o-methyltranferase, affects the
cognition process through by metabolic degradation of released
dopamine in the frontal cortex. The methionine (Met) allele, produces
enzymes which have a lower level of activity, hence lesser
degradation of dopamine, ultimately affecting cognition.5HTR2A
(His452Tyr) for our study, the tyrosine (Tyr) form of this SNP is
shown to be involved in poorer memory performance.
Methodology: The samples used in this study were collected with
informed consent of the patients and also after ethical clearance. In
the present study, genotype data was generated for the three loci for
217 Alzheimer’s type Dementia cases and 89 unaffected subjects
(age). In addition to the genotypic data, quantitative intermediate
phenotypes have been used to capture underlying heritable trait
variation and create more homogenous high-risk and low-risk groups
of subjects. Data was initially assessed for single loci association
using chi-square test and then checked for gene x gene interactions as
well as gene x quantitative trait (such as age at assessment,
psychometric scores, brain volumes) interactions using
multidimensional factorial reduction (MDR) and Generalized MDR
(GMDR) respectively. MRI data was available for 43 individuals, 24
cases and 19 controls, of the entire sample list.
Results: ApoE 4 allele showed positive association (p

PP147 GENOME-WIDE LINKAGE SCAN OF ANTISOCIAL
BEHAVIOR, DEPRESSION AND GENERAL SUBSTANCE
MISUSE IN THE UCSF FAMILY ALCOHOLISM STUDY
I. Gizer*(1), C. Ehlers(2), C. Vieten(3), H. Feiler(4), D. Gilder(2), K.
Wilhelmsen(5)
1. University of Missouri 2. Scripps Research Institute 3. California
Pacific Medical Center 4. Lawrence Berkeley National Laboratory 5.
University of North Carolina
*gizeri@missouri.edu
Introduction: Epidemiological and clinical studies suggest that rates
of antisocial behavior, depression, and substance misuse are
increased among individuals diagnosed with alcohol dependence
relative to those who are not. Given that each of these phenotypes has
demonstrated moderate evidence of heritability, the present study
conducted genome-wide linkage scans of quantitative measures of
antisocial behavior, depressive symptoms, and general substance
misuse in the University of California at San Francisco Family
Alcoholism Study.
Methodology: Participants included 1647 individuals from 713
families recruited as part of the UCSF Family Alcoholism Study.
Select scales from the MMPI-2 were used to assess antisocial
behavior (Antisocial Practices scale: ASP), depressive symptoms
(Depression scale: DEP), and general substance misuse (the revised
MacAndrew Alcoholism scale: MAC-R). Linkage analysis was
conducted using the variance components approach implemented in
SOLAR.
Results: Although no loci achieved genome-wide significance (i.e.,
LOD score > 3.3), suggestive evidence of linkage to three genomic
regions was observed that was independent of alcohol and cannabis
dependence diagnostic status: (1) evidence of linkage between
antisocial behavior and chromosome 13 at 11 cM was observed
(LOD = 2.57), (2) evidence of linkage between substance misuse and
chromosome 15 at 47 cM was observed (LOD = 3.25), and (3)
evidence of multivariate linkage between antisocial behavior, general
substance misuse, and depressive symptoms and chromosome 17 at
57-58 cM was observed (LOD = 3.16).
Conclusions: The chromosome 17 locus is located in a relatively
gene-rich region and includes several candidate genes, including
SLC6A4, PPP1R1B, PNMT, VAT1, MAPT, NEUROD2, and CRHR1
that have been studied in relation to a broad range of psychiatric
disorders such as substance dependence, mood and anxiety disorders,
ADHD, and schizophrenia suggesting potentially broad relations
between this region and psychopathology. The loci on chromosomes
13 and 15 have shown previous evidence of linkage to antisocial
behavior and substance dependence, respectively.
143
PP148 RESULTS FROM THE IMAGEN GENE X
NEUROIMAGING STUDY ON REINFORCEMENT-
RELATED BEHAVIOUR IN ADOLESCENTS
G. Schumann*, I. Consortium
Institute of Psychiatry
*gunter.schumann@kcl.ac.uk
Introduction: In the IMAGEN study we aim to identify the genetic
and neurobiological basis of individual variability in impulsivity,
reinforcer sensitivity and emotional reactivity, and to determine their
predictive value for the development of frequent psychiatric
disorders.
Methodology: Comprehensive behavioural and neuropsychological
characterization, functional and structural neuroimaging and genomewide
association analyses of 2000 14-year-old adolescents are
combined with functional genetics in animal and human models.
Results: In this presentation, we will provide examples of recent
candidate gene x neuroimaging analyses, including a study where we
show that the oxytocin receptor polymorphism rs2268494 interacts
with adverse social experiences in influencing fMRI BOLD
responses to angry faces and risk for social-affective problems. Girls
carrying the minor A-allele but not TT- genotype showed decreased
ventral striatal activity after negative experiences, and greater
vulnerability for behavioural problems. Boys with the minor A-allele
had increased medial prefrontal cortex activity and fewer emotional
problems.
Conclusions: Our findings point to a novel neurobehavioural
mechanism through which the OXTR polymorphism rs2268494
interacts with negative experiences in contributing to risk versus
resilience for social-emotional problems in adolescent boys and girls.

POSTER SESSION III
ABSTRACTS:
SPECIAL SESSION ON
SUBSTANCE ABUSE
GENETICS
144

PP149 NEUROTROPHIC TYROSINE KINASE RECEPTOR 2
(NTRK2) GENE POLYMORPHISMS AND NICOTINE
DEPENDENCE
H. Chen*(1), T. Shinkai(1), K. Utsunomiya(1), S. Sakata(1,2), K.
Yamada(1), O. Ohmori(1,3), J. Nakamura(1)
1. University of Occupational and Environmental Health 2.
Sagamigaoka Hospital 3. Wakato Hospital
*stbchen@hotmail.com
Introduction: Brain-derived neurotrophic factor (BDNF) is a nerve
growth factor that develops and maintains the neurons and is an
important regulator of synaptic plasticity in human brain. Recently,
BDNFgene has been reported to play animportant role in the
developmentof nicotine dependence(ND). BDNFacts through its
high-affinity receptor neurotrophic tyrosine kinase receptor 2
(TrkBor NTRK2) in order to supportthe survival and growth of
neurons. Animal and in vitro studies showed that either BDNF or
NTRK2 expression were modulated by nicotine. The previous studies
showed a possible association between BDNF or NTRK2and ND. In
the present study, we examinethe association between the
NTRK2gene and ND.
Methodology: We collected a total of 673 subjects from one of the
Japanese major manufacturing companies (total N = 673), with an
advantage of a relatively homogeneous background. Blood samples
and questionnaires with their smoking status were collected. We
selected the rs1187323 (5'-promoter), rs1187329 (intron), and
rs1545285 (intron) of NTRK2 geneaccording to a previous
association study, minor allele frequencies or coverage of the gene.
Results: We could not find any association between FTND score and
the three NTRK2 polymorphisms in our sample. Interestingly, we
found that after sorting the BDNF Val66Met (which was conducted
in our previous study) genotypes into 2 groups (AA vs. AG+GG), we
found a non-significant trend towards a decreased FTND score in
individuals with NTRK2 (rs1187323) A-allele carrier dose
dependently. This effect was likely only in the BDNF AA-genotypic
group.Stratified analysis of the BDNFpolymorphisms showed that the
subjects with A-alleleof rs1187323 tend to have higher riskforND,
although the statistic result does not reacha significant level (Kruskal-
Wallis Test, p=0.59).
Conclusions: Although we did not find any
significant association between ND and BDNF nor NTRK2 gene
polymorphisms respectively. Our data still suggests that BDNF and
NTRK2 genes may have some interactiveeffect on ND in Japanese
workers.
145
PP150 BIPOLAR DISORDER AND SUBSTANCE ABUSE:
GENETIC AND CLINICAL PREDICTORS OF DEPRESSIVE
OUTCOME
L. Mandelli*(1), M. Mazza(2), G. Martinotti(2), D. Tavian(3), E.
Colombo(2), S. Missaglia(2), M. Di Nicola(2), D. De Ronchi(1), G.
Negri(2), R. Colombo(3), L. Janiri(2), A. Serretti(1)
1. University of Bologna, Italy 2. Catholic University of Rome 3.
Catholic University of Milan
*laura.mandelli@unibo.it
Introduction: Little is known about factors associated with treatment
outcome of depression in Bipolar Disorder (BD). In our study we
extensively evaluated a sample of BD patients for clinical features,
including substance use disorder (SUD) comorbidity, personality
disorders and traits, and social functioning, together with
polymorphisms in 8 candidate genes for BD and response to
antidepressant treatment.
Methodology: One-hundred and thirty-one BD patients and 65
healthy controls were recruited at the Department of Psychiatry and
the Centre of Addiction at the Gemelli hospital of Rome, Italy.
Patients were characterized for demographic and clinical variables
and evaluated by the Hamilton scales for depression and anxiety
(HAMD, HAMA), the Global assessment of functioning scale
(GAF), the Temperament and character inventory (TCI), the Social
adjustment scales, self report (SASS) and the Quality of life scale
(QoL). Polymorphisms in the following genes were genotyped in
both BD patients and controls: Serotonin transporter (SLC6A4),
Serotonin receptor 2C (5HTR2C), Tryptophan hydroxylase (TPH),
Dopamine receptor D2 (DRD2,) Dopamine receptor D4 (DRD4),
Brain derived neurotrophic factors, Inteleukin 1 beta (IL1b), Nitric
oxide synthase 1 adaptor protein (NOS1AP), Transient receptor
potential channel 2 (TRPM2). Moreover, 92 patients satisfying
criteria for a depressive episode were entered in a 12-months followup
under naturalistic treatment with antidepressants, mood stabilizers
and/or antipsychotics.
Results: Comorbidity for SUD was more frequent in BD type II and
in patients with a Personality disorder, was associated with poorer
social functioning but did not impact treatment outcome. Clinical
factors associated with response to treatments were baseline severity
and the temperamental trait of Harm avoidance. A polymorphism
within 5HTR2C was found associated with BD in case-control
analysis. Trends of association were observed between haplotypes in
TPH1 and BD, and IL1b and SUD. The BDNF gene was found to
independently influence the outcome of treatment, while variants in
SLC6A4 did influence the outcome in interaction with levels of Harm
avoidance.
Conclusions: Data derived from this study confirmed an involvement
of 5HTR2C in BD as well as a potential role of TPH1. Other genes
were not associated with the risk for BD, while IL1b may play a role
in SUD. SUD and personality disorders did not impact significantly
the outcome of bipolar depression, while the temperamental trait of
Harm avoidance seem to play a critical role. Nevertheless, the effect
of Harm avoidance may be mediated by variants in the SLC6A4
gene, while it is independent from the effect of other genes. Finally,
BDNF may play a critical role in treatment outcome as well,
independently from other individual features.

PP151 DRD2 HAS BOTH TRAIT-SPECIFIC AND GENERAL
ASSOCIATION WITH MULTIPLE MEASURES OF
ALCOHOL USE AND ABUSE
J. Meyers*(1), E. Nyman(2), A. Loukola(2), R. Rose(3), J.
Kaprio(2), D. Dick(1)
1. Virginia Institute of Psychiatric and Behavioral Genetics, Virginia
Commonwealth University 2. University of Helsinki & National
Institute for Health and Welfare 3. Indiana University
*meyers.jacquelyn@gmail.com
Introduction: Alcohol consumption and related problems are a
multi-faceted set of complex behaviors. Multivariate analyses of twin
and family data a genetic architecture with many different genetic
factors influencing various aspects of current alcohol consumption
and problems. Prior analyses conducted within the Finnish
population-based twin sample, Finntwin16 (n=5,238), yielded a twin
model suggesting four latent genetic factors that account for the
genetic variance across seven measures of alcohol consumption
(frequency of drinking, frequency x quantity, frequency of heavy
drinking, frequency of intoxication, and maximum drinks in a 24
hour period) and two measures of problems (The Rutgers Alcohol
Problem Index and The Mälmö-modified Michigan Alcohol Screen
Test - MmMAST). The first two latent genetic factors loaded onto all
of the drinking measures the third latent genetic factor loaded
exclusively onto maximum drinks in a 24 hr period and The
MmMAST and the fourth latent genetic factor loaded onto the two
indices of problems.
Methodology: The present study follows up on the complex genetic
architecture seen across these measures in the twin analysis with
measured genotypic data collected on a subset of 600 individuals
from this twin sample. We conducted a series of genetic association
analyses across nine Dopamine Receptor D2 (DRD2) SNPs testing
the relationship between alcohol use/abuse candidate gene DRD2 and
the four latent genetic factor scores provided by the previously
indicated twin model.
Results: The results follow the model implicated by prior twin
analyses, where some SNPs (e.g., rs4245149) are significantly
associated across all of the genetic factor scores (p-values= 0.009-
0.02), but most significantly associated with the general latent genetic
factor score which loads onto all drinking measures (p=0.009), while
other SNPs (e.g. rs1799978) are only associated with specific genetic
factors, in this case the genetic factor which loads uniquely onto
maximum drinks in a 24hr period and the MmMAST(p=0.008).
Conclusions: Our analyses indicate that different measures of current
alcohol consumption and alcohol problems show a complex genetic
architecture there is not a single genetic factor responsible for the
phenotypic overlap between different measures of consumption and
problem use. Furthermore, careful attention must be paid to the
phenotype in efforts to “replicate” genetic effects across samples or
combine samples for meta-analyses of genetic effects influencing
susceptibility to alcohol-related outcomes.
146
PP152 EVIDENCE OF SHARED POLYGENIC RISK AMONG
SMOKING BEHAVIORS AND BODY COMPOSITION
R. Peterson*, X. Chen, J. Chen, B. Webb, H. Maes
Virginia Commonwealth University
*peterson.roseann@gmail.com
Introduction: Obesity and nicotine dependence (ND) represent
complex heterogeneous diseases which pose serious public health
problems, affecting 33 and 20 percent of Americans, respectively.
While cross-sectional studies of ND are typically supportive of a
negative relationship between smoking and body mass index (BMI),
a positive association is supported by the observations that, within
smoking cohorts, heavy smokers tend to be of increased bodyweight
compared to light smokers. A growing body of literature
demonstrates the utility of genome-wide association studies (GWAS)
for identifying single nucleotide polymorphisms (SNP) that
contribute to disease risk. The GWAS approach has been applied to
BMI and smoking behaviors (SB) using sample sizes in the tens of
thousands and yielded several putative risk variants of small effects
on individual traits. Many traits show comorbidity but most studies
do not examine common versus specific variants. The purpose of this
study was to investigate whether variants affecting BMI or SB were
common to multiple behaviors or were trait specific.
Methodology: 75 BMI and 54 SB associated SNPs were catalogued
from large-scale GWAS meta-analyses. These variants were tested
for association in n=2,802 (41% African-American) older
community-dwelling adults (68-80 years old) from the Health Aging
and Body Composition study.
Results: Current smokers had significantly lower BMI and
abdominal visceral fat than never or former smokers in males and
females (p

PP153 LATENT CLASS ANALYSIS AND HERITABILITY OF
A DEVELOPMENTAL SUBTYPE OF BIPOLAR DISORDER
B. Sharma*, E. Nwulia
Howard University
*bikashsharma222@hotmail.com
Introduction: To investigate the validity of a developmental form of
bipolar disorder (BD) characterized clinically by early age at BD
onset, alcohol use disorder, rapid-cycling, and suicidal behaviors.
Methodology: Data from participants in the U.S. Bipolar Genomic
Study (BiGS), who met the DSM-IV criteria for bipolar I disorder
(BDI) or Schizoaffective Disorder, Bipolar Type were used to
generate a discrete, one-factor model with two classes. We used
misclassification rates, sensitivity (true positive rates) and 1-
specificity (false-positive rates) tests to determine the quality of
measurement of this trait. Heritability of the derived latent class was
then estimated from 635 NIMH bipolar pedigrees.
Results: 926 out of 1000 participants in the study had complete
information on age at onset, alcoholism, suicide attempts and rapid
cycling. The prevalence of developmental BD (dBD) in the cohort
was 61%. Early age at onset as a single trait has a sensitivity of
93.3% for dBD and false positive rate (FPR) of 68%. Corresponding
values of sensitivity and FPR for alcoholism, rapid switching and
suicide attempts are: 58.6% and 28.8%; 74.4% and 29.7%; and
59.7% and 19.4%, respectively. Having all four items gave a positive
predictive value (PPV) of 97.1%. Absence of all four items has a
negative predictive value (NPV) of 96.7%.The global goodness of fit
likelihood ratio test (2 degrees of freedom) of this model was 4.864
(P < 0.09). From a sample of 635 BDI families the estimated
heritability of dBD was 0.75 (95% CI, 0.44 – 0.87).
Conclusions: Our results demonstrate the validity and heritability of
dBD, which can be characterized clinically by early age at BD onset,
alcohol use disorder, rapid-cycling, and suicidal behaviors.
Correlation with molecular markers would add further evidence to
the biological validity of dBD. Moreover, phenotypes derived
through confirmatory latent variable methods, such as dBD, could
help minimize heterogeneity complicating genetic studies of other
complex disorders.
147
PP154 UNIQUE LOCI IN THE CHRNA5/CHRNA3/CHRNB4
GENE CLUSTER ARE ASSOCIATED WITH AGE OF
REGULAR SMOKING
S. Stephens*(1), N. Hoft(1), S. Hartz(2), N. Saccone(2), L. Bierut(2),
M. Ehringer(1)
1. Institute for Behavioral Genetics 2. Washington University St.
Louis
*sarah.h.stephens@colorado.edu
Introduction: Variation in the CHRNA5/CHRNA3/CHRNB4 gene
cluster on chromosome 15 has been associated with nicotine
dependence and smoking behaviors in multiple studies including
genome-wide association studies (Bierut et al. 2007 Berrettini et al.
2008 Caporaso et al. 2009 Thorgeirsson et al. 2008) and four recent
meta-analyses (Furberg et al. 2010 Liu et al. 2010 Saccone et al. 2010
Thorgeirsson et al. 2010). Extensive genotyping of this region has
identified statistically independent nicotine dependence association
signals(Saccone et al. 2009)tagged by SNPs rs16969968
(nonsynonomous), rs578776, rs588765, and rs12914008 (rare). Two
additional independent loci have been associated with early initiation
of tobacco (Schlaepfer et al. 2008) and age of first regular use
(rs684513) (unpublished data).
Methodology: We (as part of the GEMINI consortium) designed a
large meta-analysis to examine SNPs in this region for association
with both tobacco age of initiation (AOI) and age of first regular
tobacco use (AOR). This meta-analysis included ~40,000 subjects
from 6 countries and evaluated 5 SNPs and their correlates including
rs16969968, rs578776, and rs588765. SNPs rs1948 and rs684513
were also examined due to their association with AOI and AOR
(respectively). A unified script (in SAS and R) was developed and
sent to all participating groups for local analysis of each data
set. Summary statistics were extracted from the output and metaanalysis
was carried out using PLINK (Purcell et al 2007).
Results: Preliminary results with AOR yielded significant
associations with SNPs rs578776 (Beta = 0.029, p = 0.001) and
rs684513 (Beta = 0.043, p = 0.005). Rs16969968, the most
replicated signal in this region for nicotine dependence and cigarettes
per day, was not significant for AOR.
Conclusions: These results provide important insight into the
complexity of the genetic signals in the CHRNA5/A3/B4 gene cluster,
suggesting that independent loci may contribute to the risk for
nicotine dependence (and other drug behaviors) via different
mechanisms.

PP155 TRANSLATIONAL MODELING THE GENETICS OF
ALCOHOL USE DISORDERS AND TREATMENT EFFICACY
IN A NON-HUMAN PRIMATE MODEL ORGANISM
E. Vallender*, C. Sweeney, G. Chen, D. Platt, G. Miller
Harvard Medical School - New England Primate Research Center
*eric_vallender@hms.harvard.edu
Introduction: Alcohol use disorders are a major source of public
health problems in society with significant health, economic, and
social consequences. Understanding the factors leading to these
disorders and developing treatment options has long been a major
public health initiative. Over the past several decades it has become
clear that alcohol use disorders are polygenic and numerous genes
have been identified that associate with the disease. Among these
genes and variation are OPRM1, SERT, and MAOA. While each of
these has been associated with alcohol use disorders in the past,
additional studies have had variable success in replicating the
findings in separate populations. This pattern has also been extended
to include the OPRM1 pharmacogenetic response to naltrexone
treatment. As these human studies have progressed, variation has
been identified in rhesus macaques that functionally parallels the
variation observed in humans for each of these genes. By using
specific cohorts of rhesus macaques as natural genetic models of
alcohol abuse we can better understand the true genetic factors
underlying individual susceptibility and response to treatment as well
as control for and manipulate environmental interactions.
Methodology: Male rhesus macaques have been genotyped at the
SERT promoter repeat polymorphism, MAOA promoter repeat
polymorphism, OPRM1 C77G, and several other SNPs in
serotonergic and opioidergic genes. These animals are then trained to
self-administer alcohol. Their preference for alcohol and total
consumption is measured at various concentrations. These animals
are then also treated with naltrexone at varying doses and their
responses are measured. These phenotypic measures of alcohol
consumption and naltrexone efficacy can then be analyzed in a
genetic context.
Results: The OPRM1 G77 allele is associated with increased alcohol
preference and consumption in rhesus macaques in an additive
fashion. G77 homozygotes show 40% greater alcohol consumption
across concentrations and respond to naltrexone at 30-fold lower
dosage levels. Heterozygotes show intermediate phenotypes. These
results, along with in vitro functional studies, validate and elucidate
human OPRM1 A118G polymorphism studies. This work is also
being extended to additional genes and variation. This helps to
explain a greater percentage of the overall variation seen between
animals as well as to explain variation within OPRM1 C77G
genotypes.
Conclusions: Association studies of human genetic variation
underlying alcohol use disorders have produced mixed results. Using
a non-human primate model organism that harbors alleles that
functionally parallel disease-associated alleles in humans, it is
possible to clarify these findings and develop better understandings
of the relevant genetic basis of the disease.
148
PP156 USING GENETIC INFORMATION FROM GENOME-
WIDE ASSOCIATION STUDIES IN RISK PREDICTION FOR
ALCOHOL DEPENDENCE IN TWO SAMPLES
J. Yan*(1), F. Aliev(1), K. Kendler(1), B. Webb(1), M. Schuckit(2),
J. Nurnberger Jr(3), H. Edenberg(4), J. Kramer(5), A. Goate(6), J.
Tischfield(7), D. Dick(1)
1. Virginia Institute for Psychiatric and Behavioral Genetics, Virginia
Commonwealth University 2. Department of Psychiatry, University
of California-San Diego 3. Department of Psychiatry, Indiana
University School of Medicine 4. Department of Biochemistry and
Molecular Biology, Indiana University School of Medicine 5.
Department of Psychiatry, University of Iowa College of Medicine 6.
Department of Psychiatry, Washington University School of
Medicine 7. Department of Genetics, Rutgers University
*jia.jiayan@gmail.com
Introduction: Genome wide association studies (GWAS) of alcohol
dependence (AD) have reported numerous associated variants.
However, the clinical validity of these genetic variants to
discriminate cases and controls for DSM-IV AD compared to family
history has not been assessed. The Collaborative Study on the
Genetics of Alcoholism (COGA) and the Study of Addiction: Genes
and Environment (SAGE) GWAS samples were used to examine the
aggregate impact of multiple genetic variants with small effect sizes
on clinical risk prediction using receiver operating characteristic
(ROC) curve analysis.
Methodology: Subsets of the COGA and SAGE samples were used
as gene discovery and validation samples in 3 sets of analyses.
Genetic sum scores were created by adding risk alleles of associated
SNPs in discovery samples and then assessed for their ability to
discriminate between cases and controls in independent validation
samples. The 3 analyses sets were distinguished based on methods of
selecting SNPs from GWAS results: (1) SNPs from initial GWAS
results. We used sum scores based on semi-independent SNPs
resulting from GWAS analysis in one half of the SAGE sample to
assess discriminative accuracy in the second half of the sample. (2)
SNPs from GWAS analysis that are also associated in a second
sample. A subset of individuals from the SAGE sample who were not
part of COGA was split in half. Sum scores based on SNPs that were
associated in both halves of this sample were created and used for
assessing discriminative accuracy in the COGA sample, with the idea
that SNPs that had replicated may be more likely to represent “true
positives” and enhance the predictive ability. (3) SNPs from GWAS
analysis using varying “significance” criteria. Individuals from the
SAGE sample who were not part of COGA were combined with the
COGA GWAS sample, and then split randomly in half. Subsets of
SNPs were selected from GWAS results in one half of the sample
based on p-value thresholds of 0.001, 0.01, 0.05, 0.1, 0.2, 0.3, 0.4,
and 0.5. Each subset was then used to create sum scores to assess
discriminative accuracy in the other half of the sample, testing the
hypothesis that using SNPs meeting less stringent p-value thresholds
may better detect variants of small effect. Analyses were repeated
using several random splits of the combined SAGE-COGA GWAS
sample in order to account for chance effects.
Results: ROC curve analysis using the first two SNP-selection
methods did not result in significant discriminative ability for any of
the sum scores, suggesting that the SNPs are not predicting better
than chance. Association of the sum scores and the individual SNPs
in the samples that were used for ROC curve analysis did not yield
significant results, which explains the lack of significant
discriminative accuracy in these samples. The presence or absence of
family history for AD was a better classifier of case-control status,
with a significant area under the ROC curve (AUC) of 0.686 (95% CI
= 0.654, 0.718, p < 0.001) in COGA and 0.614 (95% CI = 0.584,
0.643, p < 0.001) for a parental history of AD-related traits in SAGE.
The third SNP selection method using p-value thresholds of 0.01 to
0.5 did yield significant AUC estimates ranging from 0.535 for SNPs
with p-value < 0.01 to 0.573 for SNPs with p-value < 0.5. AUC
results did not show a consistent pattern across all random splits of
the sample.
Conclusions: This study shows that these SNPs have limited clinical
utility and that family history is currently a better predictor of AD.
This illustrates the need for further development of prediction panels
that incorporate replicated variants contributing to risk for AD.

PP157 EPIGENETIC MODIFICATIONS IN THE WAKE-
PROMOTING BASAL FOREBRAIN MAY CONTRIBUTE TO
INSOMNIA DURING ALCOHOL WITHDRAWAL
S. Lodhi*, R. Sharma, D. DeRoode, M. Thakkar
Harry S Truman Memorial Veterans Hospital, Department of
Neurology, University of Missouri
*shafilodhi@�����.com
Introduction: Insomnia and associated sleep disturbances are
amongst the most profound and protracted symptomsof alcohol
withdrawal (Roehrs and Roth, 2001). Importantly, convincing
evidence exist to suggest that insomnia observed during alcohol
withdrawal is a predictor of relapse to alcoholism (Brower, 2003).
Recently, we have demonstrated that chronic alcohol exposure causes
insomnia by reducing the expression of genes involved inadenosine
release and transmission and increasing the activation of wakepromoting
neurons in the cholinergic basal forebrain (BF; Sharma et.
al., 2010). Histone acetylation is a key epigenetic mechanism that is
believed to control gene expression. Increased histoneacetylation
opens the chromatin and enhances gene expression, whereas reduced
histone acetylation packs thechromatin and reduces gene expression.
Does chronic ethanol exposure reduce histone acetylation in the BF?
We performed two experiments to address this issue. Our first
experiment examined histone acetylation in the BF ofethanol
dependent rats. Our second experiment monitored sleep in ethanol
dependent rats following bilateraladministration of the histone
deacetylase (HDAC) inhibitor, Trichostatin-A (TSA) into the BF
Methodology: Experiment 1:Male Sprague Dawley rats (200-300
gm) were divided into two groups: controls (N=5)and experimentals
(N=5). Ethanol dependency was achieved by using the
Majchrowicz’s method as described previously (Sharma et al., 2010).
In brief, at light onset, a priming dose of 5 g/Kg of ethanol (35% v/v)
wasintragastrically administered to the experimental animals.
Subsequent doses were adjusted based on theintoxication status of the
animals and administered every 8 hr for 4 days. Controls were
intragastricallyadministered with isocaloric water (10 ml/Kg) at same
time points for 4 days. On withdrawal day, 12 hr after the last dose of
ethanol, the rats were euthanized and brains removed, blocked and
the BF region was sectioned andprocessed for acetylated histone
immunohistochemistry. Experiment 2: Under aseptic conditions and
inhalation anesthesia, male Sprague Dawley rats (200-300 gm) were
stereotaxically implanted with sleep recording electrodes along with
bilateral guide cannulas targeted towards the BF (Thakkar et al.,
2010). Following post-operative recovery and habituation, ethanol
treatment was initiated and continued for 4 days as described above.
On withdrawal day, at light onset, the animals were randomly divided
into two groups. Group 1 animals were bilaterally microinjected with
TSA (10 nmol/1µL/each side) into the BF. Group 2 animals were
bilaterally microinjected with the vehicle (10% DMSO/1 uL/each
side). Subsequently undisturbed sleep-wakefulness was continuously
recorded for 24 hr. Results: Experiment 1:Our results suggests that
there was a significant reduction (p

PP159 MULTIVARIATE GENOME-WIDE ASSOCIATION
ANALYSES OF NEUROPHYSIOLOGICAL PHENOTYPES IN
ALCOHOLISM
S. Kang*(1), N. Manz(1), M. Rangaswamy(1), J. Kramer(2), L.
Almasy(3), V. Hesselbrock(4), S. Kuperman(2), J. Nurnberger(5), H.
Edenberg(5), J. Tischfield(6), B. Porjesz(1)
1. SUNY Downstate Medical Center 2. University of Iowa 3. Texas
Biomedical Research Institute 4. University of Connecticut Health
Center 5. Indiana University School of Medicine 6. Rutgers
University
*������������������������
Introduction: Event-related oscillations (EROs) represent highly
heritable neuroelectrical correlates of human perception and
cognitive performance, and are markers of risk for alcoholism. To
identify genetic variants associated with EROs, we performed a
genome-wide association study (GWAS). While statistical methods
used for GWAS data analyses have been largely univariate (single
phenotypes), multivariate analyses have advantages over univariate
analysis whether or not there is correlation between phenotypes. To
investigate the advantages of information from correlated
phenotypes, we conducted multivariate GWAS for delta and theta
ERO and P3 amplitude
Methodology: All neurophysiological phenotype values were
extracted from the target case of the Visual Oddball experiment. The
two EROs were calculated at the parietal midline channel (Pz) for the
delta band (1-3 Hz) and the frontal midline channel (Fz) for the theta
band (3-7 Hz). The extracted measures were derived from a 300-700
ms post stimulus window, bounding the visual P3 event. P3
amplitude was measured as the voltage difference between the prestimulus
baseline (100 ms prestimulus) and the largest positive going
peak in the latency window 300-600 ms after stimulus onset at the
parietal midline electrode (Pz). Illumina HumanHap 1M chips in
1399 unrelated European Americans drawn from the Collaborative
Study on the Genetics of Alcoholism (COGA) were used for analysis.
After quality control procedures, we regressed delta and theta ERO
and P3 amplitude phenotypes on age in each gender and included
alcohol dependence as a covariate.
Results: We compared the p values of univariate and multivariate
analyses results for the SNPs in genes previously found to be
associated with alcohol dependence or neurophysiological
phenotypes. SNPs in SNCA, ADH4, TACR3, NPY2R, ACN9, GRM8,
CHRM2, OPRK1, PENK, GABRG3, CHRNA7, PDYN, CDH13 and
PRKG2 genes that showed no significant association with the
neurophysiological phenotypes in univariate analysis were
significantly associated with the phenotypes in multivariate analysis.
For example, univariate analysis p values for rs1316749 in NPY2R
are greater than 0.1 for all three phenotypes, whereas multivariate
analysis p value for this SNP is less than 0.008. Another example is
rs7656323 in PRKG2. The univariate p values for theta, delta, and P3
are 2×10-4, 0.99, and 0.02, respectively. The bivariate p value for
theta and P3 is 4×10-7 while the multivariate p value for theta, delta,
and P3 is 2×10-6.
Conclusions: These results underscore the advantage of using
multivariate over univariate GWAS by utilizing the correlated
phenotypic information to prioritize significant genes.
150
PP160 IDENTIFICATION OF RARE VARIANTS UNDER AN
ALCOHOLISM SUSCEPTIBILITY LINKAGE PEAK IN A
COGA FAMILY USING WHOLE EXOME SEQUENCING
M. Kapoor*(1), J. Wang(1), A. Hinrichs(1), S. Bertelsen(1), J.
Budde(1), A. Agrawal(1), J. Tischfield(2), L. Almasy(3), M.
Schuckit(4), L. Bierut(1), A. Goate(1)
1. Washington University School of Medicine 2. Department of
Genetics/Human Genetics Institute, Rutgers University 3.
Department of Genetics, Texas Biomedical Research Institute 4.
Department of Psychiatry, University of California, San Diego
*kapoorm@psychiatry.wustl.edu
Genetic factors may explain as much as 60% of the variance in risk
for alcoholism. Genomewide association studies of alcoholism only
accounted for small proportion of this variance. We undertook whole
exome sequencing to investigate the possible contribution of rare
coding variants to susceptibility to alcohol dependence. Finding
missing heritability through rare variants is conceptually easy, as it
can involve closer scrutiny of genes and regions of interest.
Combining the power of traditional linkage studies with next-gen
sequencing can help find missing heritability in the form of rare and
novel variants. Multiple chromosomal regions have been linked to
alcohol dependence and other key phenotypes in our previous studies.
In the present study, we have sequenced a trio (two alcohol
dependent and one non-dependent control) selected from a large
family that has many alcoholic subjects, and showed a very high NPL
score on chromosome 2 with DSM-IV diagnosis. We used the
SureSelect Human All Exon Kit and protocols provided by Agilent to
capture exons, and performed paired-end sequencing on the Illumina
GA2 platform. More than 95% of the exome was captured with >8X
read depth. A total of 722 variants on chromosome 2 were detected in
the affected parent and offspring, but were not present in the
unaffected parent. Among these, 83 variants lie under linkage peak
and were coding variants. Out of 83 variants, 22 variants had minor
allele frequency (MAF) less than 5% in dbSNP and 7 were novel. We
validated these 29 variants by genotyping in rest of family members,
and in about 4000 cases and controls. Preliminary association
analysis using these rare and novel variants helped us to identify 6
variants in 6 genes which may be associated with alcohol
dependence. Further we sequenced these 6 genes using the targeted
sequence capture approach in case-control dataset to determine
enrichment of non-synonymous rare variants among alcohol
dependents. Functional analysis of these non-synonymus variants
present in these genes genes and variants will help us in better
understanding of underlying biological mechanisms for alcohol abuse
and dependence.

PP161 EPIGENETIC CONTROL OF GENE EXPRESSION IN
ALCOHOLIC BRAIN
I. Ponomarev*, S. Wang, L. Zhang, R. Harris, R. Mayfield
Waggoner Center for Alcohol and Addiction Research and the College
of Pharmacy, University of Texas at Austin
*����������������������
Recent evidence from brain transcriptome studies suggested that
changes in gene expression associated with alcohol drinking
phenotypes are, at least in part, controlled by global epigenetic events
(chromatin modifications). We tested this hypothesis by comparing
several epigenetic marks in frontal cortex of human alcoholics and
control cases. We first examined DNA methylation status of the
endogenous retroviral sequences, Long Terminal Repeats (LTR).
LTRs are actively repressed by DNA methylation, and their
transcriptional activity is a sensitive marker of global DNA
hypomethylation. We found that DNA in brains of alcoholics is less
methylated, which was consistent with the up-regulation of LTR
transcripts. We next tested the hypothesis that up-regulation of some
genes in alcoholic brain is associated with more tri-methylation of
histone 3 at Lysine 4 (H3K4me3), a marker of active transcription.
Our chromatin assays provided evidence supporting this hypothesis.
A combination of chromatin immunoprecipitation and qRT-PCR
showed more global H3K4me3 in alcoholics. H3K4me3 at the
promoters of several genes was also increased in alcoholics. In
addition, we examined the expression of several genes that form
transcription co-repression complexes (TCC). TCCs link histone
deacetylase to specific DNA sites at gene promoters, resulting in
histone deacetylation and transcriptional repression of the affected
genes. Most genes that form TCCs were up-regulated in alcoholics,
and the number of up-regulated TCC genes was significantly greater
than chance (P

PP163 GENETIC TESTING FOR THE SUSCEPTIBILITY OF
ALCOHOL DEPENDENCE: INTEREST AND CONCERNS
D. Scott *, E. Nwulia, V. Headings, J. Kwagyan, G. Cain, V.
Marshall, N. Kalu, C. Williams, R. Taylor
Howard University College of Medicine
*d_m_scott2@howard.edu
Introduction: Recent advances in the search for susceptibility genes
of alcohol dependence (AD) are generating growing interest for
possible genetic risk assessment of at-risk relatives and the general
population. The purpose of this study is to examine the level of
interest and concerns for predictive genetic testing for susceptibility
to AD.
Methodology: Respondents are 304 African American adult
residents of Washington, DC metropolitan area who were recruited
through public advertisement. All participants were administered the
Genetic Psycho-Social Implication (G-PSI) questionnaire, which
surveyed their interests in hypothetical genetic testing for AD, as
well as their perception of ethical, social and legal concerns
Results: More than 85% of participants were interested in predictive
genetic testing; however, persons with higher education (p< 0.002)
and income (p< 0.008) were less willing to receive
testing. Perception of AD as a deadly disease (48.60%) and curiosity
to know for their children (47.90%) were most prevalent reasons for
interest in testing. Among those not interested in testing, belief that
they were currently acting to lower their risk was the most prevalent
reason for their decision. Although several concerns were raised, the
most widely expressed concern in the entire sample was accuracy of
testing (35.50%). Other notable concerns between participants
interested in testing and those not interested in testing were: method
of testing (p< 0.01), side effects (p

PP165 CHRNA5-CHRNA3-CHRNB4 GENE CLUSTER IS
ASSOCIATED WITH SEVERAL NICOTINE DEPENDENCE
RELATED TRAITS
J. Wedenoja (1,2,3,4),. Broms(1,4),. Largeau(2,4),. Korhonen(1,4),
J. Pitkäniemi(1,4), K. Vuokko(1), A. Häppölä(1), K. Heikkilä(4), K.
Heikkilä(1), S. Ripatti(2,4), S. Sarin(2), O. Salminen(5), T. Paunio
T(2,4,6), M. Pergadia(7), J. Kaprio(1,2,4), A. Loukola(1,4)
1. Department of Public Health, Hjelt Institute, University of Helsinki
2. Institute for Molecular Medicine Finland FIMM, University of
Helsinki and National Institute for Health and Welfare 3. Department
of Medical Genetics, University of Helsinki 4. National Institute for
Health and Welfare 5. Division of Pharmacology and Toxicology,
Faculty of Pharmacy, University of Helsinki 6. Department of
Psychiatry, Helsinki University Central Hospital 7. Washington
University School of Medicine, Saint Louis
Reguar tobacco smoking represents one preventable cause of
mortality, but is often associated with psychiatric and substance
disorder co-morbidities. Especially the nicotinic acetylcholine
receptor gene cluster on chromosome 15q24-25 has been established
in nicotine dependence (ND) and other smoking-related traits.
Here, we utilized a study sample of twin pairs concordant for history
of cigarette smoking as well as their first-degree relatives. This series
with an extensive dataset of 30 smoking-related phenotypes was
ascertained from the Finnish Twin Cohort, involving adult twins born
between 1938 and 1957, with baseline in 1975 at age 18 and over.
First, we analyzed 15 tagging SNPs in the CHRNA5-CHRNA3-
CHRNB4 cluster on 15q24-25 in 1428 individuals (mostly
twins) from 735 families. We detected significant associations with a
variety of traits measuring ND, the strongest signal emerging for
DSM-IV ND symptoms (best p=0.000009; rs2036527 near
CHRNA5). Additionally, rs11636753 in CHRNB4 showed association
with regular drinking (p=0.003) and the co-morbidity of depression
and ND (p=0.003).
Second, we performed genome-wide association analysis in a subset
of 1125 twins with 3,858,597 markers from Illumina 670k chip and
HapMap2-based imputation data. In addition to CHRNA5-CHRNA3-
CHRNB4 cluster, strongest signals were detected for DSM-IV ND
symptoms on chromosome 2q33 (best p=0.0000008; near CD28) and
8q21 (best p=0.000001; near STMN2), for cigarettes per day (CPD)
on chromosome 16p12 (best p=0.000000007; near SYT17), and
sensation felt after smoking the first cigarette on chromosome 8p21
(best p=0.0000004; near GFRA2). Interestingly, also association with
number of depression symptoms was detected on chromosome 4q31
(best p=0.00000004; in ZNF827).
153
PP166 UNDERSTANDING THE RELATION BETWEEN AGE
AT FIRST DRINK AND DRINKING TO COPE MOTIVES: A
TWIN STUDY
K. Young-Wolff*
University of Southern California
*kellyyw@gmail.com
Introduction: Prior research indicates that individuals who begin
drinking at an early age are at a greater risk for using alcohol to cope
with negative mood states; however, the mechanisms underlying this
association remain unclear. One possibility is that early drinking
directly increases risk for drinking to cope (DTC). Alternatively, the
association between early drinking and DTC may be attributable to
overlapping familial sources (shared environmental or genetic
factors). No prior genetically informative study has investigated the
sources of covariation underlying the early drinking-DTC
association.
Methodology: Early age at first drink (< age 15) was assessed using
structured clinical interviews in a sample of 7566 male and female
participants aged 19-56 years from the Virginia Adult Twin Study of
Psychiatric and Substance Use Disorders. Data on DTC was obtained
using the mood management scale of the Alcohol Use Inventory
(AUI). The sources of the covariation between early first drink and
DTC were estimated using both a matched case-control analysis of
twin pairs discordant for early drinking and bivariate twin modeling.
Results: Approximately 22% of participants reported drinking before
the age of 15 years. Regression analyses indicated that early drinking
onset was associated with significantly higher scores on DTC.
Results from co-twin control analyses and bivariate structural twin
models of early drinking onset and DTC indicated that a substantial
portion of the early drinking-DTC association was attributable to
overlapping genetic variation.
Conclusions: Individuals who reported they began to drink before
age 15 were more likely to endorse drinking to cope with negative
mood. Our results suggest that this early drinking-coping association
largely reflected genetic factors that contribute to the etiology of both
characteristics.

PP167 ASSESSMENT OF KNOWLEDGE AND ATTTIUDE
OF CARE GIVERS OF PEOPLE WITH SCHIZOPHRENIA
AND BIPOLAR DISORDER ABOUT ROLE OF GENETICS IN
DISORDER CAUSATION
Y. Balhara*
Lady Hardinge Medical College And SSK Hospital
*ypsbalhara@gmail.com
Introduction: Role of gentic factors in multifactor causation of
major mental disorders including schizophrenia and bipolar disorders
is well established. However the knowledge and understanding of the
care givers of those suffering from these conditions has never been
studied in India. Such a knowledge is likely to shape the attitude and
belief of these individuals towards the patients and his/her siblings.
Such information would be of help in planning ppropriate
psychoeducation for thes eindividuals.
Methodology: We assessed the care givers of patients with
schizophrenia or bipolar disorder (as per DSM IV TR) for their
knowledge and understanding on the role of genetic factros of these
disorders. Consecutive patients with either of these conditions were
selected fr the study following informed consent. Total of 200 care
givers (100 each of schizophrenia and bipolar disorder) were
included in the study. The assessments were carried out using a
questionnaire developed specifically for this purpose. The
questionnaire is aimed at assessmen tof knoledge of the care givers
on the role of genetic factors in causation of these to disorders. It also
assessed attitude of the care givers towards possibility of these
disorders among children of the patients. In between group
comparisons were made between the two care givers of two
disorders. Non -parametric analyssi was carried out using
MannWhitney U test and Kriskall Wallis test. Level of statistical
significance was kept at p< .05.
Results: The findigns of the current study bring out interesting facts.
Care givers of patients with schizophrenia as well as bipolar disorder
have limited knowledge about role of gentic fcators in their
causation. Also the information is limited on heritability of these
disorders. This in turn seems to shape their attutude toards the
children of the patients.
Conclusions: It is impoartant to assess and intervene regarding the
knowledge and attitude of care givers of patients with schizophrenia
and bipolar disorders towards role of gentic factors in their causation.
154
PP168 STATISTICAL PHASE VERSUS MOLECULAR
PHASE RESOLUTION: HTR2C HAPLOTYPE AND SUICIDE
ATTEMPT IN FEMALE PATIENTS WITH MAJOR
PSYCHOSES
V. de luca*, C. Teo, B. Mckenzie, C. Zai, J. Kennedy
CAMH
*vincenzo_deluca@camh.net
Introduction: Haplotype is the combination of phased allele on the
same chromosome. When we genotype a sample of unrelated patients
the phase in unknown in the subjects with two or more heterozygous
genotypes. The parental genotype can be helpful to reconstruct the
phase however the molecular techniques available to resolve the
phase are not currently used in studies aimed to develop genetic
testing. The most common statistics used to infer the phase in
unrelated subjects is the PHASE program. The aim of this study is to
compare the inferred phase with the phase resolved by the means of
the ABI 3130 using the same genotype data.
Methodology: We analyzed a sample of 250 females with affective
and non affective psychoses assessed for suicide attempt lifetime
using the PHASE program for the HTR2C haplotype.
Results: When we considered the molecular phase none of the
haplotypes was associated with suicide attempt (p>0.05). However
many double heterozygous subjects were misdiagnosed in terms of
haplotype pairs when we used the PHASE algorithm compared
to the molecular phase.
Conclusions: This simple result suggests that future sequencing
analysis should investigate the utility of the molecular phase
haplotypes in the development of genetic testing in psychiatry

PP169 ALCOHOLIC BEVERAGE PREFERENCE: AN
EPIDEMIOLOGICAL AND TWIN STUDY
ECIP
L. Hack*(1), J. Myers(3), H. Maes(1,2,3), K. Kendler(1,3)
1. Department of Human and Molecular Genetics, Virginia Institute
for Psychiatric and Behavioral 2. Massey Cancer Center, Virginia
Commonwealth University 3. Department of Psychiatry, Virginia
Institute for Psychiatric and Behavioral Genetics, Virginia
Commonwealth University
*hacklm@vcu.edu
Introduction: Alcoholic beverage preference, generally defined as
one’s most heavily or frequently consumed alcoholic beverage, has
been associated with particular lifestyle habits, social consequences,
and medical outcomes. The present study sought to replicate and
expand some of these findings in a twin sample by assessing the risk
of developing alcohol use disorders (AUDs) and related measures
based on alcoholic beverage preference in both the same individual
and the co-twin. Additionally, while there is an extensive genetic
epidemiological literature on frequency of consumption, few studies
have considered specific alcoholic beverage intake when assessing
the magnitude of genetic and environmental contributions to
consumption measures. Thus, we assessed the factors contributing to
twin resemblance for most frequently consumed beverage, or
alcoholic beverage preference.
Methodology: The sample consisted of 5489 twins (3200 males and
2289 females) from the Virginia Adult Twin Study of Psychiatric and
Substance Use Disorders (VATSPSUD) identified through the
population-based Virginia Twin Registry. Clinically trained
interviewers collected data on beverage preference (wine, beer, or
spirits), AUDs, consumption measures, and other psychiatric
conditions, including antisocial personality disorder (ASPD),
generalized anxiety disorder (GAD), and major depression (MD).
The authors conducted multivariate regression in SAS and structural
twin modeling in Mx .
Results: The risk of AUDs, symptoms of these disorders,
consumption measures, and ASPD is lowest in wine preference
drinkers. The significant co-twin findings showed a similiar trend.
Beer drinkers are the most likely to engage in high and frequent
consumption, while distilled spirit drinkers are at the greatest risk for
alcohol dependence, more impairing symptoms of AUDs, and ASPD.
For all three preference categories, the tetrachoric correlations
between twins suggest a stronger genetic influence on preference in
females and a stronger shared environmental influence in males.
When we proceeded to formal univariate twin modeling, we found
that genders could be equated for beer and distilled spirits without
loss in model fit but not for wine. We are currently attempting to find
the most appropriate multivariate model for quantity of consumption
of the three beverages in a second twin sample, the Virginia 30,000
(VA30K). This analysis has proven to be challenging due to the
competitive nature of consumption of these beverages.
Conclusions: Firstly, preference for particular alcoholic beverages
leads to differential risk for the development of AUDs, symptoms of
these disorders, consumption measures, and ASPD. These findings
have implications for classifying alcohol dependent individuals into
subtypes and for the application of personalized treatments for AD.
Secondly, the relationship between preference and differential risk
appears to be influenced by familial factors. Finally, beverage
preference is substantially influenced by genetic and shared
environmental factors, the nature of which may differ across the
genders. This finding suggests that refininement of our consumption
phenotypes may be beneficial for identifying risk genes in genomewide
association studies.
155
PP170 HUMAN µ-OPIOID RECEPTOR GENE VARIANT
A118G (ASN40ASP): LACK OF ASSOCIATION WITH
ALCOHOL DEPENDENCE OR ALCOHOL CONSUMPTION
N. Rouvinen-Lagerström(1), J. Lahti*(2), H. Alho(1,3), M. Aalto(1,
11), L. Kovanen(1), T. Partonen(1), K. Silander(4), D. Sinclair(1), K.
Räikkönen(2), J. Eriksson(5,6,7,8), A. Palotie(5, 9, 10)
1. Department of Mental Health and Substance Abuse Services,
National Institute for Health and Welfare 2. Institute of Behavioural
Sciences 3. Research Unit of Substance Abuse Medicine, University
of Helsinki and Helsinki University Central Hospital 4. Unit of
Public Health Genomics, National Institute for Health and Welfare,
and Institute for Molecular Medicine FIMM 5. National Institute for
Health and Welfare 6. Department of General Practice and Primary
Health Care, University of Helsinki 7. Unit of General Practice,
Helsinki University Central Hospital 8. Folkhalsan Research Centre,
Biomedicum Helsinki, University of Helsinki 9. Wellcome Trust
Sanger Institute 10. Broad Institute of Harvard and MIT 11.
Department of Psychiatry, South Ostrobothnia Hospital District
*jari.lahti@helsinki.fi
Introduction: The human µ-opioid receptor (Mu Opioid Receptor,
MOR) has been implicated in the reinforcement, tolerance and
withdrawal effect of many substances of abuse including
alcohol. The OPRM1 gene (Opioid receptor Mu 1 gene) carries a
functional A118G (Asn40Asp) polymorphism. When compared with
the 118A (Asn40) allele, the 118G (Asp40) allele has been reported
to result in increased binding of β-endorphin, which is one of the
important physiological mediators of alcohol-induced
reinforcement. Several studies have linked A118G polymorphism to
individual differences in alcohol-induced stimulation and alcohol
consumption in experimental settings. The molecular epidemiological
studies on association of A118G polymorphism and alcohol use
disorders have, however, given contradictory results. The focus of
this study was to test the possible association of A118G
polymorphism and alcohol use disorders and alcohol consumption in
large cohort-based study populations.
Methodology: : The association between the OPRM1 A118G
(Asn40Asp, rs1799971) polymorphism and alcohol use disorders and
alcohol consumption was analyzed using three different populationbased
samples: i) a Finnish cohort study, Health 2000, with 503
participants with DSM-IV diagnosis for alcohol dependence and/or
alcohol abuse and 506 age and sex-matched controls ii) a Finnish
cohort study, FINRISK (N=2360), and iii) the Helsinki Birth Cohort
Study (N= 1384), which lacked diagnosis-based alcohol information,
but included detailed information on alcohol consumption.
Results: We found no statistically significant differences in
genotypic or allelic distribution between controls and subjects with
alcohol dependence or abuse diagnoses. Also no significant effects
were observed between the A118G genotype and alcohol
consumption.
Conclusions: These results suggest that A118G (Asn40Asp)
polymorphism is not associated alcoholism or alcohol consumption
and thus may not have a major effect on the development on alcohol
use disorders.

PP171 FROM SUBSTANCE USE TO SUBSTANCE
DEPENDENCE: THE ROLE OF EXECUTIVE FUNCTIONING
J. Vandever*(1,2), N. Friedman(2), S. Young(2,3), A. Miyake(1), R.
Corley(2), J. Hewitt(1,2), M. Stallings(1,2)
1. Department of Psychology and Neuroscience, University of
Colorado 2. Institute for Behavioral Genetics, University of Colorado
3. Department of Psychiatry, University of Colorado
*joanna.vandever@colorado.edu
Introduction: Individual differences/deficits in executive cognitive
functioning (EF) have been hypothesized to play an important role in
substance use disorders. In a study of adolescent twins, genetic
influences on substance use and substance dependence vulnerability
were found to be related to cognitive processes common across
inhibiting, updating, and shifting tasks (Common EF; Vandever et al.,
in preparation). Although our measure of substance use (number of
substances used repeatedly) was less heritable than our measure of
substance dependence vulnerability (average dependence symptoms,
or total number of DSM-IV criteria endorsed divided by the number
of substances used repeatedly), the genetic correlation between
substance use and Common EF was greater in magnitude than the
genetic correlation between substance dependence vulnerability and
Common EF. This preliminary finding suggests that genetic variation
in substance ‘use’ may be more strongly related to Common EF than
genetic variation in dependence vulnerability. For the present study
we followed up on this finding by using more detailed measures of
substance use histories to better understand the role of executive
functions across the developmental course of substance
use/dependence.
Methodology: We conducted a biometrical analysis of adolescent
twins (16–18 years) who had completed a battery of nine laboratory
assessments of executive functioning and a structured clinical
interview on substance use. Three substance-related transitions were
identified: 1) use versus no use; 2) among users, problem use versus
no problems (assessed by the endorsement of DSM-IV ‘symptoms’
of dependence but no dependence diagnosis); and 3) among problem
users, the progression to substance dependence (assessed by meeting
DSM-IV criteria for dependence on at least one substance). For initial
analyses factor scores were obtained for Common EF.
Results: Consistent with our expectations, mean levels of Common
EF were significantly lower when comparing users to non-users; but
no significant mean differences were found when comparing problem
users to non-problem users, and when comparing problem users with
those progressing to dependence.
Conclusions: Our findings are consistent with the hypothesis that
individual differences/deficits in executive function distinguish
between users and non-users (i.e., who initiates substance use and
who doesn’t), but may play a lesser role in the transitions to problem
use and dependence. However, the equivalence of cross-trait twin
correlations between Common EF and these categorically scored
substance transitions indicate that environmental influences, rather
than genetic factors, underlie these associations. Analyses utilizing a
latent measure of Common EF and continuous measures of substance
use stages will be explored.
156
PP172 META-ANALYSIS OF SEROTONIN TRANSPORTER
GENE PROMOTER POLYMORPHISM (5-HTTLPR)
ASSOCIATION WITH ANTIDEPRESSANT EFFICACY
S. Porcelli*, C. Fabbri, A. Serretti
Institute of Psychiatry, University of Bologna
*stefano.porcelli@yahoo.it
Introduction: In the last decade the serotonin transporter gene
promoter polymorphism (HTTLPR) was likely the most studied
genetic variant as predictor of antidepressant response. Nevertheless
results are not consistent across studies and previous meta-analysis,
since various factors seem to modulate its effect on antidepressant
response.
Methodology: We systematically reviewed literature, selecting 18
studies performed on Caucasians (3746 subjects)and 12 on Asians
(1429 subjects). We tested two phenotypes - remission and response
rates - and two genotype comparisons - ll versus ls/ss and ss versus
ll/ls - using the Cochrane review manager. Evaluations were
performed separately for SSRIs and mixed/other drugs and for
Caucasians and Asians. Possible clinical modulators were
investigated.
Results: In Caucasians, we found an association between l allele and
both response (p=0.004), and remission (p=0.004) in the SSRI group.
Only a marginal association between l allele and remission (p=0.04)
survived pooling together mixed antidepressant treatments. In Asians,
a small effect of HTTLPR on remission for mixed antidepressants
was detected (p=0.01). Gender, age and age at onset modulated the
association in Caucasians. Gender, age and depression severity at
baseline modulated the association in Asians.
Conclusions: In Caucasians HTTLPR is likely a predictor of
antidepressant response and remission, whilst in Asians it does not
appear to play a major role.

PP173
Withdrawn
157
PP174 INTERACTION BETWEEN COMT HAPLOTYPES
AND CANNABIS USE ON THE SEVERITY OF PSYCHOTIC
SYMPTOMS
M. Zanoni*(1), C. Bonetto(1), A. Lasalvia(1), D. Cristofalo(1), E.
Ira(1), K. De Santi(1), V. Marangon(2), R. Riolo(3), D. Collier(4), M.
Ruggeri(1), S. Tosato(1)
1. Department of Public Health and Community Medicine, Section of
Psychiatry and Clinical Psychology, University of Verona 2. CMHC
Mirano 3. CMHC Camposampiero 4. Social, Genetic and
Developmental Psychiatry, Institute of Psychiatry
*martina.zanoni@univr.it
Introduction: One of the environmental factors extensively studied
in relation to schizophrenia susceptibility is cannabis use, at least
among genetically vulnerable individuals. One attractive gene to
analyze in a gene×environment interaction is catechol-Omethyltransferase
(COMT), which is involved in the catabolism of
catecholamines and is the main enzyme controlling the metabolism of
dopamine in prefrontal cortex. Three different common functional
haplotypes have been described in COMT, called low pain sensibility
(LPS), average pain sensibility (APS), and high pain sensibility
(HPS), with APS and HPS haplotypes showing significant reductions
in enzymatic activity in comparison to the LPS haplotype. It was
found that high activity haplotypes (LPS) fastly reduce the levels of
dopamine in the prefrontal cortex, leading to worse negative
symptoms. In the current work, in a first episode psychosis cohort,
our aim is to demonstrate that cannabis users carrying LPS COMT
haplotype experience worse negative symptoms than cannabis
users carrying at least one of the high activity haplotypes (either HPS
or APS). Moreover, among LPS haplotype carriers, we hypothesize
that cannabis users experience worse negative symptoms than non
users.
Methodology: The study has been conducted in the broader
framework of the Psychosis Incident Cohort Outcome Study
(PICOS), a multisite research conducted in Veneto (Italy), aiming at
characterizing first-episode psychosis patients. We used a case-only
design comprising about 200 first-episode psychosis patients.
Psychopathology was collected using PANSS and information on
drug use in the year before the first contact with the Psychiatric
Service for psychosis was collected by using the CDUS (Clinical
Drug Use Scale) (information was obtained from both the subject and
the relatives and interviewed the case-manager when needed).
Genetic analyses are being performed investigating COMT
haplotypes as defined by rs4680, rs4633, rs4818, and rs6269.
Results: Two hundred Caucasian patients (92% from Italy and 8%
from East Europe, mainly Romania) gave their DNA for the genetic
analysis. This sample included 49 (24.5%) patients with
schizophrenia (ICD10-F20), 108 (54.0%) with non schizophrenic non
affective psychosis (ICD10-F21-F29), and 43 (21.5%) with affective
psychosis (ICD10-F30-F32). 51% are males with a mean age of 30
years. At present the genotyping analyses are still ongoing and no
preliminary results are available, yet.
Conclusions: Our study may help to clarify the role of genetic
interaction in the clinical presentation of psychoses at the onset. In
particular, while previous studies mainly investigated the impact of
GxE interaction in either schizophrenia or bipolar disorder, to our
knowledge this is the first study focusing on first-episode psychosis
patients, thus encompassing diagnostical boundaries. Moreover, the
perspective of a symptom-based approach is attractive because it may
provide a model for studying the heterogeneity of psychosis,
enhancing the ability to identify the underlying pathophysiology of
the illness.

PP175 DNA METHYLATION PROFILE IN THE HUMAN
PERIOD 1 GENE PROMOTER AND ITS RELATION TO
STRESS AND ALCOHOL DRINKING
C. Wong*, F. Carvalho, B. Ruggeri, J. Mill, S. Desrivières, G.
Schumann
MRC Social, Genetic & Developmental Psychiatry Centre, Institute
of Psychiatry, King's College London
*c_peng.wong@kcl.ac.uk
Introduction: Research over decades has demonstrated the
importance of circadian rhythms in controlling gene expression. Our
recent analyses have indicated that the Period (PER) genes might be
involved in regulating alcohol drinking behaviour, in addition to their
role in circadian rhythms. Mutation of Per2 results in increased
alcohol drinking and mutation of Per1 enhances stress-induced
alcohol drinking in mice, for which the data supports the association
studies conducted in humans (Spanagel et al., 2005 Li et al.,
submitted). Moreover, gene expressions of Per1 and Per2 are known
to be modulated by alcohol, and that the expression of Per1 is also
modulated by stress. These data suggest Per1 may participate in the
adaptations of environmental factors such as stress, via various
genetic and epigenetic mechanisms. To test this hypothesis, we
investigate the relationship between the variations in DNA
methylation profile at the Per1 promoter and the stress- and alcoholrelated
behaviours in humans.
Methodology: We took a sub-sample of n=700 14-year old
adolescents from the FP6-funded IMAGEN project, for which
genetic, neuroimaging and behavioural data such as stressful life
events and alcohol drinking are available. Whole blood DNA samples
of these individuals were used to analyse DNA methylation patterns
in the PER1 promoter region using Sequenom © MALDI-TOF
technology.
Results: In our first step, we analysed methylation status of a small
region within the Per1 promoter. We identified variations at 6 CpG
units with mean methylation levels ranging from 0.16 to 0.49, up to a
maximum methylation level of 0.77. Inter-individual variations in
methylation at some CpG units were found. We are currently
analysing the relationship between methylations at the identified CpG
units and genetic variations around the analysed region. In addition,
we are conducting association analyses of methylation and brain
activation profiles subjected to impulsivity- and emotion-related
neuroimaging tasks among the same 700 individuals.
Conclusions: We found inter-individual variations in DNA
methylation patterns within the promoter of PER1. At present, we are
investigating the significance of such variations in stress- and alcohol
drinking-related behaviours, using the behavioural and neuroimaging
phenotypes available in the IMAGEN project. The comparison of
methylation levels at the PER1 promoter region will provide insight
on the importance of epigenetic modification on PER1 function and
its impact on human behaviour.
158
PP176 ASSOCIATION STUDY OF GABRG2
POLYMORPHISMS WITH ALCOHOL USE AND SUICIDAL
BEHAVIOUR IN SCHIZOPHRENIA PATIENTS
C. Zai*, A. Tiwari, G. Zai, V. de Luca, J. Kennedy
CAMH
*cchzai@yahoo.ca
Introduction: γ-aminobutyric acid (GABA) is produced in areas of
the brain implicated in schizophrenia, and several genes coding for
GABAA subunits, including GABRG2 encoding the γ2 subunit, are
clustered at 5q31-q35, a chromosomal region associated with
schizophrenia in genome scan studies. We recently reported
GABRG2 to be associated with schizophrenia in our schizophrenia
case-control and family samples (Zai et al, 2009).
Methodology: We tested eight single nucleotide polymorphisms
spanning GABRG2 for association with alcohol use, and with suicidal
behaviour, and with both combined in our schizophrenia sample of
European ancestry (N=179).
Results: We did not find GABRG2 to be significantly associated
with history of alcohol dependence or suicide attempt. We found
rs209356 to be associated with history of combined alcohol
dependence and suicide attempt (p=0.03). We also found an
interaction between history of alcohol dependence and rs211037 in
severity of suicidal behaviour (p=0.04).
Conclusions: Taken together, the results of the present study suggest
GABRG2 may be involved in suicidal behaviour and alcohol use in
schizophrenia patients, but replications are required. These results
may help in the discovery of novel treatments for alcoholism and/or
prevention of suicide. We plan to analyze other GABA system genes
with these phenotypes.

PP177 A PROMOTER VARIANT IN THE NET (SLC6A2)
GENE PREDICTS BOLD RESPONSE TO GUSTATORY
ALCOHOL CUES
S. Blaine*(1), H. Haughey(2), E. Claus(1), K. Hutchinson(1)
1. 1The MIND Research Network. 2. 2University of Virginia School
of Medicine, Dept. of Psychiatry and Neurobehavioral Sciences
*sblaine@mrn.org
Because alterations within the SLC6A2 gene contribute to differences
in craving for alcohol, the present study sought to examine the
influence of allelic variations in the SLC6A2 gene on variation in
neural responses to alcohol cues. The SLC6A2 gene encodes for the
sodium-dependent noradrenaline (NET) transporter. NET transports
norepinephrine and dopamine from the synapse back to presynaptic
cytosol, for later storage and release. We collected DNA samples and
fMRI data using a cue-elicited craving paradigm in 326 heavy
drinkers. The sample included heavy drinkers, with average alcohol
dependence lifetime and current symptom counts of 6 ± 3, mean
Alcohol Dependence Scale score 18 ±8, and mean Alcohol Use
Disorders Identification Test score of 19 ±8. The pattern of BOLD
activity in response to the alcohol taste cue task replicated previous
findings, with activation in the alcohol minus litchi contrast mainly in
the pathways where NET transporters are highly expressed. These
pathways include connections among the brain stem, amygdala,
hippocampus, caudate, and frontal medial gyri. BOLD activation in
incentive and control regions in response to gustatory alcohol cues
was predicted by 13 of the 60 SNPs in the SLC6A2 gene tested. Each
of the SNPs associated with BOLD activation are in one of two LD
blocks, one at the 3’ end of the gene and one toward the 5’ end of the
gene. One SNP that predicted BOLD response, rs2242446, is a
promoter variant in the gene that has been previously linked to
medication response. These findings replicate and extend recent
research suggesting that genetic variation at the NET locus may
underlie the expression of alcohol phenotypes, including craving
responses.
159
PP178 ALCOHOL MISUSE IN BIPOLAR DISORDER A
SYSTEMATIC REVIEW AND META-ANALYSIS OF
COMORBIDITY RATES: IMPLICATIONS FOR GENETIC
ANALYSIS
A. Di Florio, M. van den Bree, N. Craddock
MRC Centre for Neuropsychiatric Genetics & Genomics
Introduction: One of the specific objectives of the Psychiatric
GWAS Consortium is the analysis of comorbidities between major
psychiatric disorders and alcohol/substances use disorders. The
possibility of heterogeneity and bias across studies is an important
issue in the definition of phenotypes suitable for genetic analyses. Of
all DSM IV axis I disorders, bipolar disorder (BD) has been reported
to be the most strongly linked with alcohol use disorders (AUD).
AIM: To assess the current state of knowledge on the prevalence of
AUD in people affected by BD and to explore possible sources of
heterogeneity.
Methodology: Studies reporting the comorbidity or co-occurrence
rates of AUD in people affected by BD were identified through
database searches. Meta-analytic techniques were employed to
aggregate data on lifetime comorbidity. Possible sources of
heterogeneity were explored using univariate and multivariate
random effects meta-regression. Funnel plots were employed for
diagnosing certain forms of publication bias.
Results: Of 1639 studies initially identified, 41 included in the
systematic review. 12 papers from the ancestor research were
selected and included. Data on 9535 subjects with BD were included
in the meta-analysis. Overall, AUD affected more than 1 in 3 subjects
with BD, although a large variability across studies was reported.
Variability was largely explained by geographical location and
methodological differences across studies. Gender affected
comorbidity rates as well, with AUD rates 1.5-2 times higher in men
than women.
Conclusions: The heterogenic nature of comorbidity between BD
and AUD is underscored by the current literature. Analyses aimed to
identify convincing genotype-phenotype associations should account
for the high variability in the clinical assessment across samples. This
meta-analysis produced results which corroborate the findings of a
great deal of the previous work in this field, which has found a high
prevalence of AUD in BD and a strong association between male
gender and AUD. However, we reported a large variability between
studies that has not previously been described. Moreover, metaregression
analyses indicated a significant effect of methods of
ascertainment and geographical location of the studies in the
prevalence estimates. These results seem to be consistent with other
research on AUD in the general population.

PP179 ASSOCIATION BETWEEN THE NOREPINEPHRINE
TRANSPORTER GENE AND ALCOHOL DEPENDENCE IN
EUROPEAN AMERICANS
H. Haughey*, C. Seneviratne, A. A.S. Joshi, B. Johnson, M. Li
University of Virginia School of Medicine, Dept. of Psychiatry and
Neurobehavioral Sciences
*hmh8f@virginia.edu
Introduction: Alcohol dependence is a chronic, complex, polygenic
debilitating disease that causes economic, personal, and family
hardship worldwide. Individual differences in response to the acute
effects of alcohol, as well as risk for alcohol dependence (AD), are
known to be influenced by both genetic (G) and environmental (E)
factors, along with their GxE interactions. Past and present
preclinical and clinical studies have suggested that the norepinephrine
(NE) system plays a role in alcohol consumption, sensitivity, craving,
and may affect drug and alcohol reward and dependence. To date,
there are both negative and positive association studies of the NE
transporter (NET; slc6a2) gene and alcohol dependence. A most
recent study in a large cohort of German subjects has found a positive
association between alcohol dependence and slc6a2. Therefore, the
purpose of the present study was to replicate these findings in a
sample of Americans of European descent.
Methodology: We tested two promoter SNPs and 6 other NET SNPs
one from each haplotype block to interrogate the NET gene region
(rs192303, rs47958, rs36030, rs1800887, rs36021, rs11648486,
rs17841327, rs2242446). The study included 271 AD and 327 control
subjects whose population admixture was tested with a panel of 24
ancestral informative markers. The AD was diagnosed using DSM-
ІV, and those with co-morbid Axis 1 diagnoses other than nicotine
dependence were excluded. Associations of the SNPs with AD were
assessed at both the individual SNP and haplotype levels.
Results: Results demonstrated a gender specific association of two
SNPs with AD at the individual SNP level. The interaction between
male gender and A allele and AA genotype of NET intron 1 SNP
rs17841327 were significantly associated with AD (X 2 =5.443,
P=0.020 and X 2 = 4.855, P=0.028, respectively). Additionally, the
interaction between male gender and C allele of another intron 1 SNP
rs36030showed a trend for developing AD (P=0.074).
Conclusions: : Taken together, these data suggest that
polymorphisms within the NET gene are significantly associated with
the development of AD in Caucasian men. The gender differences
that we detected warrant further examination of gender specific
autonomic system differences associated with alcohol addiction.
(Research supported by NIAAA grant K01-AA015331(HMH),
Grants 7 U10 AA011776-10, 1 N01 AA001016-000, 7 R01
AA010522-12, and 5 R01 AA012964-06 (BAJ) and Grants R01
DA012844 and R01 DA013783 (MDL).
160
PP180 ABSENCE OF SIGNIFICANT ASSOCIATION OF
ALLELE A9 OF DOPAMINE TRANSPORTER GENE
DAT1/SLC6A3 WITH ALCOHOL WITHDRAWAL SEIZURE
OR DELIRIUM TREMENS IN THE INDIAN POPULATION:
A CASE-CONTROL ASSOCIATION STUDY
B. Kishore*(1, 2), P. Murthy(1), S. Jain(1), V. Benegal(1), K.
Thennarasu(1), M. Purushottam(1), D. Subhashree(1), H. Kiran(1)
1. Department of Psychiatry, National Institute of Mental Health and
Neurosciences 2. 2North Western Mental Health
*brijkishore@aol.com
Introduction: The allele A9 of dopamine transporter gene (DAT1;
SLC6A3) has been implicated for its role in complicated alcohol
withdrawal as manifested by alcohol withdrawal seizures (AWS) and
delirium tremens (DT). However there have been both positive and
negative studies in literature. We investigated the role of the DAT1
gene in an Indian alcohol dependent population for the first time.
Methodology: A group of 106 alcohol dependence cases (52 alcohol
dependent males with simple alcohol withdrawal and 54 with
complicated alcohol withdrawal) and 104 normal healthy male
controls were genotyped and compared in a case-control design, after
assessing them with strict inclusion and exclusion criteria and
informed consent.
Results: In contrast to the positive studies showing higher frequency
of allele A9 carriers in alcohol dependent patients with complicated
withdrawal, our study in the Indian population reveals that the
frequency of allele A9 carriers [ƒ (A9+)] was nominally higher in
simple alcohol withdrawal group [ƒ (A9+) = 0.25] rather than
complicated alcohol withdrawal group [ƒ (A9+) = 0.22] and normal
healthy male controls [ƒ (A9+) = 0.22]. Our results also show that the
frequency of individuals carrying the allele A9 [ƒ (A9+)] was higher
in group of alcoholics [ƒ (A9+) =0.27], compared to the normal
healthy controls [ƒ (A9+) =0.22], but the association was not
statistically significant.
Conclusions: To conclude there is absence of any significant
association of allele A9 of DAT1 VNTR polymorphism with
complicated alcohol withdrawal or alcohol dependence cases in
Indian population. We propose further studies with larger sample
sizes including female alcohol dependent patients as well as familybased
studies to assess the role of DAT1 VNTR polymorphism in
complicated alcohol withdrawal and alcohol dependence.

PP181 A PILOT STUDY ON THE MOLECULAR EFFECTS
OF DEPRESSION AND ALCOHOLISM ON NEURAL STEM
CELLS
C. May, P. Sathyan, S. Majumder
The University of Texas MD Anderson Cancer Center, The
University of Texas Graduate School of Biomedical Sciences
Depression and alcoholism are both mental illnesses that are poorly
understood at the molecular level. Here we began to examine the
effect of these two illnesses on neural stem cells (NSCs). Here we
show that a novel function of the transcriptional repressor REST is to
maintain the self-renewal and multipotency of mouse NSCs. Primary
neurospheres obtained from E12 brains of transgenic mice expressing
Egfp through the Rest promoter/enhancer sequences (Rest-Egfp)
showed the co-expression of REST, EGFP and NSC stemness
markers.
Culturing NSCs under differentiation conditions decreased REST and
stemness marker expression and increased the expression of
differentiation markers of neuronal, glial, and oligodendrocyte
lineages, indicating that REST-expressing NSCs are multipotent.
RESTpositive, but not REST-negative NSCs, showed self-renewal
for several passages. Knockdown of REST in REST-positive NSCs
increased REST target gene expression and decreased their selfrenewal
capacity. Thus, a new function of REST is to maintain
normal NSC self-renewal and multipotency.
We further show that NSCs subjected to treatments mimicking either
a depressive environment (i.e. cortisol) decreased REST levels, while
NSCs subjected to treatments mimicking alcoholic environment
increased REST levels. This suggests that though on the behavioral
level these two diseases may have overlapping syndromes,
molecularly they affect neural stem cells differently and that
alcoholic environment may induce NSC self-renewal, an effect not
studied before.This work was partly supported by grants from the
NCI (CA97124 and CA81255 to S.M.).
161
PP182 SEROTONIN TRANSPORTER MRNA LEVELS IN LL
GENOTYPE CARRIERS AS A GENOMIC BIOMARKER FOR
QUANTITATIVE ASSESSMENT OF DRINKING SEVERITY
IN ALCOHOLICS
C. Seneviratne(1), N. Ait-Daoud(1), X. Wang(2), M. Li(1), B.
Johnson(1)
1. Departments of Psychiatry and Neurobehavioral Sciences 2. Public
Health Sciences,
Introduction: Paucity of sensitive biomarkers to quantify transient
changes in alcohol consumption level remains a critical barrier for the
development of efficacious therapeutic agents to treat alcoholism.
Recently, in an 11-week, randomized, placebo-controlled, double
blind trial of 283 alcohol dependent individuals, Johnson et al (2011) 1
demonstrated that ondansetron was efficacious at reducing the
severity of drinking (measured as drinks/drinking day, DDD) in
alcoholics carrying the LL compared with the LS/SS genotype of
serotonin transporter gene, 5’-HTTLPR.
Methodology: Using peripheral blood samples from a cohort of 41 of
these subjects, we determined if there was a relationship between
mRNA expression level of the 5’-HTTLPR genotypes (measured at
weeks 0, 4, and 11) and self-reported alcohol consumption following
treatment with either ondansetron (4 µg/kg twice daily; N=19) or
placebo (N=21). Using a mixed-effects linear regression model, we
analyzed the effects of DDD and 5-HTTLPR genotypes, on mRNA
expression levels within and between the ondansetron and placebo
groups.
Results: We found a significant three-way interaction effect of DDD,
5′-HTTLPR genotypes, and treatment, on mRNA expression levels
(p=0.0396). Among ondansetron but not placebo recipients there was
a significant interaction between DDD and 5′-HTTLPR genotype
(p=0.0385 and p=0.7938, respectively). In the ondansetron group,
DDD was associated positively with mRNA levels at a greater rate of
expression alteration per standard drink in those with the LL
genotype (slope=+1.1698 in Ln scale).
Conclusions: We suggest that the combination of 5-HTTLPR - LL
genotype and 5’-HTTLPR mRNA expression levels might be a
promising and novel biomarker to quantify drinking severity in
alcoholics treated with ondansetron.

PP183
WITHDRAWN
162
PP184 THE GENETICS OF RECREATIONAL DRUGS
ABUSE IN BIPOLAR PATIENTS INVESTIGATED
THROUGH A GENOME WIDE MOLECULAR PATHWAY
ANALYSIS
A. Drago, A. Serretti
Institute of Psychiatry, University of Bologna
Introduction: Addiction to recreational drugs is a major health issue
worldwide 1. Genetics may shape the risk of addiction to recreational
drugs, and consistent genetic evidence is gathering 2. Knowing in
advance who holds a genetic liability to addiction may help clinicians
to tailor relevant clinical choices. This issue may be crucial in
specific subpopulation of patients for whom addiction to drugs may
worsen the prognosis. Bipolar patients may be at risk
Methodology: We analyzed the STEP-BP sample 4 at enrollment.
Having a present or a past history of abuse for opiates, LSD, cocaine
or amphetamines was the principal outcome. A three step analysis
was conducted: first, a genome wide molecular pathway analysis
identified the molecular pathways differentially regulated in bipolar
patients with or without addiction to recreational drugs. Second, the
genes within those molecular pathways were ranked according to the
strength of association with the principal outcome and their relevance
within each pathway. Third, one gene per pathway was further
genome wide investigated for epistatic interactions. R and plink
served for the analysis.
Results: 1821 subjects were initially enrolled and genotyped. 1697
subjects had compete data on drug addiction, 115 out of whom were
recreational drugs abusers. 366125 SNPs were available for analysis
after quality check. Pathway associated with cell signaling
(hsa04080, hsa02010 and hsa04020), cell movement (hsa04514,
hsa04512, hsa04510 and hsa04810), cell replication and cell death
(hsa04210, hsa05222 and hsa05215) were significantly associated
with the principal outcome. Hsa04080, hsa04514 and hsa04510 were
further investigated. Epistatic interactions of interest were:
rs11644075 ( GRIN2A a glutamatergic receptor) vs rs7702070 (less
than 1kb away from the GDNF (glial cell derived neurotrophic
factor)) (OR = 17.41), rs2267787 ( GRIN2A ) vs rs6837383 (SEPT11
septin 11, involved in cytokinesis and vesicle trafficking)) (OR =
15.48), rs9932138 ( GRIN2A ) vs rs2070699 ( EDN1 endothelin 1)
(OR=15.93); rs919751 ( PDGFRB platelet-derived growth factor
receptor) vs rs7945377 ( SHANK2 ankyrin) (OR=15.67), rs12365943
(less than 2 kb from DDX10 RNA elicase) vs rs1864971 ( PDGFRB )
(OR=13.15), rs1864971 ( PDGFRB ) vs rs9948162 ( LOC100130480
hypothetical protein ) (OR=18.51); rs10748138 ( CNTN1 contactin 1)
vs rs557725 (less than 1kb from the KCNU1 potassium channel)
(OR=13.87), rs11178018 ( CNTN1 ) vs rs1855640 (less than 1kb
from ANKRD30A ankyrin) (OR=14.34), rs11610114 ( CNTN1 ) vs
rs2714016 ( SLC39A11 metal ion transporter) (OR = 14.00). All
associations had p levels < 1e-4 (default for plink genome wide
epistatic interactions)
Conclusions: We conducted a genome wide molecular pathway
analysis in a sample of bipolar patients in order to investigate the
genetics of addiction in this subpopulation. We brought some results
that enlarge the genetic perspective on the disorder including genes
related to cell movement and cell survive. These results are partially
consistent with previous findings as well, as for example glutamate 5
and the ankyrins

PP185 CHARACTERIZATION OF THE NEURON-SPECIFIC
ENOLASE GENE (ENO2) AS A SUSCEPTIBLE GENE OF
HEROIN ADDICTION
H. Liao(1), D. Liao(2), M. Cheng(3), C. Lai(4), C. Chen(4)
1. Institute of Biotechnology and Graduate Program of
Biotechnology in Medicine, National Tsing-Hua University 2. Bali
Psychiatric Center, Department of Health, Executive Yuan 3.
Department of Psychiatry, Yuli Mental Health Research Center, Yuli
Veterans Hospital 4. Division of Mental Health and Addiction
Medicine, Institute of Population Health Sciences, National Health
Research Institutes
Heroin addiction is a complex mental disorder resulting from
interactions between genetic and environmental factors. Identifying
the susceptible genes of heroin addiction is essential for better
treatment and prevention of heroin abuse and addiction. We
previously found the expression of neuron-specific enolase gene
(ENO2) in the lymphoblastoid cell lines (LCL) was down-regulated
in heroin addicts in a gene expression profiling analysis. We verified
this finding using real-time quantitative PCR and Western blot
analysis in this study. To assess whether the ENO2 gene is associated
with heroin, we compared the allele and genotype frequencies of 3
single nucleotide polymorphisms (SNPs, rs11064464, rs3213433 and
rs10849541) between 532 male heroin addicts and 369 male controls.
No significant differences in the allele or genotype frequencies of
these 3 SNPs were detected between these two groups. Nevertheless,
we identified a haplotype (T-C-G) derived from these 3 SNPs
significantly under-represented in heroin addicts compared to control
group (72.7% vs 75.9%, p

PP187 INCUBATION OF HEROIN CRAVING IS NOT
ASSOCIATED WITH ALTERATIONS IN BDNF, TRKB, AND
MECP2 EXPRESSION AND SIGNALING IN NUCLEUS
ACCUMBENS, DORSAL STRIATUM, AND MEDIAL
PREFRONTAL CORTEX
Q. Liu, F. Theberge, S. Fanous, C. Pickens, E. Goldart, B. Hope, Y.
Shaham
BRC/NIDA/IRP
Introduction: Nucleus accumbens (NAc) BDNF signaling plays an
important role in incubation of cocaine craving (time-dependent
increases in cue-induced cocaine seeking after withdrawal). Here, we
studied whether incubation of heroin craving is associated with
alterations of expression in BDNF and phosphorylation of TrkB (the
BDNF receptor) in NAc, as well as dorsal striatum (DS), and medial
prefrontal cortex (mPFC) and DNA methylaiton of BDNF promoters
in central amygdala (CEA). We also assessed expression and
phosphorylation changes of MeCP2, a transcription suppressor that
modulates BDNF expression.
Methodology: We trained groups of rats to self-administer heroin
(0.075 mg/kg/infusions, 6 h/d for 10 d) or saline (a control
condition). After 1, 11 and 30 withdrawal days, we dissected the
NAc, DS, and mPFC and measured protein levels of BDNF, TrkB,
TrkB phosphorylation (pY816 site), MeCP2, and MeCP2
phosphorylation (pS80 and pS421sites). In other groups of rats, we
assessed cue-induced heroin seeking in 30-min extinction tests after
1, 11, or 30 withdrawal days.
Results: As in previous studies, cue-induced heroin seeking
progressively increased or incubated after withdrawal. This
incubation was not associated with changes in either protein or
mRNA levels of BDNF and MeCP2 in NAc, DS, and mPFC. BDNF
promoters are hypomethylated in CEA of both heroin and saline
treated rats.
Conclusions: Incubation of heroin craving is not associated with
changes in BDNF and MeCP2 signaling in NAc, DS, and
mPFC. Based on previous studies on the role of BDNF in incubation
of cocaine craving, the present data suggest that the cellular
mechanisms of incubation of cocaine and heroin craving are likely
different.
164
PP188 COCAINE REGULATION OF THE CART GENE IS
MODULATED IN PART BY DIFFERENTIAL REGULATION
OF THE NRSF TRANSCRIPTION FACTOR
P. Myers, S. Gillies, K. Haddley, H. Burrell, S. Vasiliou, V. Bubb,
A. Warburton, A. Savage, J. Quinn
Molecular and Clinical Pharmacology, Institute of Translational
Medicine, University of Liverpool
Introduction: The CART (cocaine and amphetamine-regulated
transcript) peptides are widely distributed in the CNS and are
involved in regulating multiple processes, including modulation of
dopamine and endocrine systems, aspects of reward, food intake and
addiction. CART has recently been identified as a transcriptional
target for negative regulation by Neuron Restrictive Silencing Factor
(NRSF), also termed Repressor Element-1 Silencing Transcription
factor (REST). NRSF is a factor we have demonstrated as a key
regulator of other neuropeptides including Substance P, NKB and
AVP. NRSF is also implicated in adult neurogenesis, epilepsy,
cognition and Scitzophrenia. Cocaine treatment is known to upregulate
the expression of CART, as well as a second NRSFregulated
neuronal gene, brain derived neurotrophic factor (BDNF).
However, despite our current knowledge of cocaine-mediated
regulation of CART and BDNF, it has yet to be clarified whether
cocaine modulates NRSF. We set out to investigate the impact of
cocaine treatment upon NRSF and CART expression in the human
SH-SY5Y neuroblastoma cell line.
Methodology: Cells from the human neuroblastoma cell line SH-
SY5Ywere treated with 1µM and 10µM cocaine, at 4hrs and 24hrs,
followed by measurement of NRSF and CART mRNA expression
through real time polymerase chain reaction (RT-PCR). NRSF
mRNA expression was further investigated using quantitative
polymerase chain reaction (qPCR). We proceeded with an
investigation into the binding of NRSF to its recognition sequence
(NRSE) within the CART and BDNF promoter regions in response to
cocaine; through chromatin immunoprecipitation (ChIP).
Results: Cocaine treatment was found to significantly decrease
NRSF mRNA expression, in an exposure-duration and concentration
dependant manner. This reduction in NRSF correlated with an
increase in CART mRNA. Furthermore, we demonstrate by
chromatin immunoprecipitation, that cocaine treatment markedly
reduces NRSF binding to both the CART and BDNF promoter
Conclusions: These findings indicate that cocaine has the capacity to
increase expression of CART via modulation of the NRSF
transcriptional regulatory system. Together with our previous data on
NRSF modulation of several neuropeptides and transmitters we are
beginning to understand the functional significance of the network of
genes modulated by NRSF in response to various challenges. This
allows for a better understanding of the combinatorial action of
peptides in regulatory processes such as addiction, endocrine
function, the stress response, depression, epilepsy and modulation of
dopamine systems.

PP189 GENE-GENE INTERACTION IN DIFFERENT
BIOLOGICAL PATHWAYS IN A SAMPLE OF
CRACK/COCAINE BRAZILIAN PATIENTS
A. Negrão(1), A. Pereira(2), C. Guindalini(3), G. Messas(1), R.
Laranjeira(4), J. Krieger(2), H. Vallada(1)
1. Program of Genetics and Pharmacogenetics, Department and
Institute of Psychiatry, University of São Paulo Medical School 2.
Laboratory of Genetic and Molecular Cardiology/LIM-13, Heart
Institute (InCor), University of Sao Paulo Medical School 3.
Department of Psychobiology, Universidade Federal de São Paulo
(UNIFESP) 4. Alcohol and Drug Research Unit, Psychiatry
Department, Federal University of São Paulo
Genetic susceptibility to crack/cocaine addiction is less studied than
other drug addictions although there are several single-locus positive
association studies. Similarly to other complex disorders, odds ratios
derived from those studies are low and there is a paucity of studies in
the field investigating gene-gene interactions. Clinical and
experimental data indicate the expression of genes associated with
dopaminergic brain reward systems as well as biological rhythms,
cortical modulation of mesolimbic function, pharmacokinetics of
cocaine among others that may render subjects susceptible to cocaine
addiction. We used nonparametric analytical methods to unravel
gene-gene interactions in genes associated with different biochemical
pathways in patients with crack/cocaine addiction. A total of 699
inpatients and outpatient who met ICD10 diagnosis of cocaine
dependence and screened unaffected normal controls (n=886) were
genotyped for 29 markes int the following genes: Dopamine receptor
D2 (DRD2), Dopamine transporter gene (DAT), Catechol-Omethyltransferase
(COMT), Dopamine beta-hydroxylase (DBH), Gprotein-coupled
receptor kinase 3 (GRK3), Period (PER) 1 and 2;
and, Gluthatione-S-tranferese-Pi (GSTP1). To examine potential
gene-gene interactions we applied the Multifactor Dimensionality
Reduction (MDR) and parameters were set to ten-fold leave-one-out
crossvalidation and a search of all possible four loci interactions. A
model that contained one marker each of the DAT/DBH/PER/GRK3
genes had the best fit with a crossvalidation consistency of 9/10 and a
testing balance accuracy of 61% and resulted in a odds ratio of 3.9
(3.1 - 4.7). Markers in those genes had failed to be detected in the
past as being associated with the cocaine status in previous papers
using this very same sample. Graphical representations of this
epistatic model in a entropy generated model in the same MDR
software showed that DBH and PER interaction contributed to a
decreased level of entropy whereas the DAT and GRK3 genes had
main effects that did not contribute in the same way to the epsitatic
result generated by the program. We demonstrate that analytical tools
that addressed epistasis can detect loci that were not associated with
cocaine addiction in single-locus studies and can broaden the picture
of susceptibility genes in cocaine addiction.
165
PP190 GENOME-WIDE ASSOCIATION STUDY (GWAS) OF
ALCOHOL DEPENDENCE (AD) AND RELATED TRAITS IN
THE IRISH AFFECTED SIB PAIR STUDY OF ALCOHOL
DEPENDENCE (IASPSAD)
A. Adkins*(1), L. Hack(1), B. Webb(2), M. Riemers(3), D.
Patterson(5), D. Walsh(6), C. Prescott(4), D. Dick(1,2), K.
Kendler(1,2), B. Riley(1,2)
1. Virginia Institute for Psychiatric and Behavioral Genetics,
Department of Human and Molecular Genetics, Virginia
Commonwealth University 2. Virginia Institute for Psychiatric and
Behavioral Genetics, Department of Psychiatry, Virginia
Commonwealth University 3. Department of Biostatistics, Virginia
Commonwealth University 4. Department of Psychology, University
of Southern California 5. Shaftesbury Square Hospital 6. Health
Research Board
*adkinsae@vcu.edu
Introduction: The powerful, systematic, and unbiased genome-wide
association study (GWAS) has been successful in identifying
replicated susceptibility variants for numerous complex diseases,
including psychiatric disorders. Only 3 individually genotyped casecontrol
GWAS of AD have been published. We report here the
completion of data collection and QC for a fourth in samples from the
IASPSAD.Our study has the advantage that our sample is clinically
homogeneous and richly phenotyped. In addition to being a
reasonably powered individual GWAS of AD, our study will also
increase by ~20% the total genotyped case/control data available for
AD.
Methodology: Our sample consists of 1050 Irish cases and affected
siblings drawn from the IASPSAD and diagnosed using DSM-IV
criteria. The majority of the sample was genotyped on the Affymetrix
V6.0 array, while promising markers will be genotyped using
Taqman assays in the remaining cases. 2000 Irish population controls
were genotyped on the same platform by the Wellcome Trust Case
Control Consortium 2 (WTCCC2) and the Broad Institute.
Results: 99.7% of our sample has Birdseed call rates >95%. A
rigorous, novel QC method developed at the Virginia Institute for
Psychiatric and Behavioral Genetics involving factor analysis of QC
metrics and visual inspection of false color microarray images is
being applied to our data. Primary analysis will include allelic
association testing for AD using maximum likelihood methods to
correct for the non-independence of sibs and false discovery rate to
correct for multiple testing, and will be completed Spring-Summer
2011. Our full sample has > 78% power to detect effect sizes for AD
of 1.2-1.3 with minor allele frequencies of 0.2-0.3. Through
collaborations, we have access to multiple independent AD GWAS
samples to attempt replication of our findings and conduct a metaanalysis.
Secondary analyses will include testing for association with
several quantitative traits within AD cases, including initial
sensitivity, tolerance, maximum daily drinks, and a factor score for
withdrawal.
Conclusions: Along with previous AD GWAS data, our data will
provide the opportunity to identify replicable associations that can be
followed up with functional studies in model organisms within the
context of the Virginia Commonwealth University Alcohol Research
Center (VCU-ARC).

PP191 BDNF MODERATES THE ASSOCIATION BETWEEN
MATERNAL PRENATAL SMOKING AND OFFSPRING
EXTERNALIZING BUT NOT INTERNALIZING DISORDERS
A. Talati*, M. Weissman, S. Hodge, P. Wickramaratne, S. Hamilton
Columbia University Medical Center
*at2071@columbia.edu
Introduction:
Introduction: Maternal smoking during pregnancy is associated with
a number of adverse psychiatric and behavioral outcomes among
their offspring1-2. The biological underpinnings of these associations
however remain unclear. We examined the role of the brain derived
neurotrophic factor (BDNF) in this pathway, based on the cumulative
evidence that (a) BDNF plays a critical role in neuronal survival and
differentiation, processes disrupted by overstimulation of nicotinic
receptors during fetal development; (b) nicotine exposure may be
able to regulate BDNF gene expression via epigenetic modification
(methylation)3; and (c) BDNF levels correlate inversely with the
level of nicotine exposure among adult smokers 4. We tested the
hypothesis that subjects who were exposed to prenatal smoking and
had lower BDNF function would be at the greatest risk for aberrant
neurocircuit development, and thus show greater rates of disorders
related to behavioral control.
Methodology: The analysis is based on 221 offspring (70 exposed;
141 unexposed) who were followed for approximately 20 years
through four assessment waves. Prenatal history, which included
information on maternal smoking and other substance use during
pregnancy, was assessed at the first wave (year 1). Exposure was
classified based on whether or not the mother smoked 10 or more
cigarettes daily while pregnant. Offspring outcomes were then
measured prospectively at years 2, 10 and 20 using the age
ageappropriate version of the Schedule for Affective Disorders and
Schizophrenia (SADS). Final diagnoses were made using the bestestimate
procedure, blind to exposure status or previous assessments.
BDNF activity was assessed by the genotype at the functional
polymorphism rs6265 (val66met) which is associated with
differential secretion levels of the protein; four additional single
nucleotide polymorphisms (SNPs) were also examined: rs4923463,
rs11030104, rs7103411, and rs2049045.
Results: Prenatal smoke exposure was associated with increased risk
for drug use disorder (DUD), alcohol use disorder (AUD), and
conduct disorder (CD), but not with major depressive disorder
(MDD) or any anxiety disorder. BDNF gene variation was not
independently associated with any outcomes. However, offspring
who had the low-functioning BDNF variant (defined as having one or
more met encoding alleles at rs6265) and were exposed in utero,
showed a two- to three-fold increase in the rates rates of AUD (p =
.03), DUD (p = .09), and CD (p = .005), than offspring who were
val/val and/or unexposed. Similar patterns were obtained for the other
tested SNPs except rs7103411. There were no gene-by-exposure
interactions for MDD or anxiety outcomes, for nonpsychopathological
drug or alcohol use. The above associations could
not be accounted for by maternal smoking outside of pregnancy,
alcohol use, or antisocial personality.
Conclusions: BDNF plays an important role in fetal development of
neural circuitry. Offspring who already have lower levels BDNF and
are then exposed to further prenatal insults such as smoke exposure
may be most vulnerable to disorders that depend on these circuits. It
should be borne in mind that these results point to a general
vulnerability to a spectrum of externalizing problems rather a specific
DSM disorder. Future research should therefore continue to examine
multiple outcomes, as well as outcomes at multiple thresholds, in
order to further delineate the specificity of these mechanisms.
166
PP192 GENETIC VARIATION IN HEROIN DEPENDENCE,
BINGE DRINKING AND CIGARETTE SMOKING
C. Barta*(1), N. Nemeth(1), Z. Demetrovics(2), R. Urban(2), J.
Farkas(2), N. Torma(2), A. Eisinger(2), A. Magi(2), M. Kapitany-
Foveny(2), P. Sarkozy(3), M. Sasvari-Szekely(1)
1. Institute of Medical Chemistry, Molecular Biology and
Pathobiochemistry, Semmelweis University 2. Institute of
Psychology, Eotvos Lorand University 3. Department of
Measurement and Information Systems, Budapest University of
Technology and Economics
*csaba.barta@eok.sote.hu
Introduction: Neural networks within the reward system play a key
role in the development of substance dependence. Variations in
candidate genes coding for receptors, transporters and metabolizing
enzymes involved in these pathways have been implicated for
association with substance use disorder.
Methodology: A total of 32 SNPs were genotyped on the Applied
Biosystems Open Array Real-Time PCR Platform in three Hungarian
cohorts. N=300 heroin dependent patients (HD) on methadone or
suboxone maintenance therapy, N=300 university students (US)
phenotypically characterized in detail for alcohol consumption habits
and N=300 high school students aged 16 to 18 (HS) phenotypically
characterized in detail for smoking habits. The studied genetic
variations included SNPs in cholinergic receptors (CHRNA3/4/5,
CHRNB3), dopaminergic (DRD2, DRD4), serotonergic, opioid,
cannabinoid and GABAergic receptors, transporters and metabolizing
enzymes, alcohol and aldehyde dehydrogenase genes, as well as
some HPA axis gene variants.
Results: Significant genetic effects were observed within the three
groups. Certain genotypes were related to good versus poor response
to substitution therapy. SNPs influencing alcohol drinking patterns
and smoking habits were also identified.
Conclusions: These results might prove useful in the individualized
choice of therapy for heroin dependent patients or to prevent the
development of substance use disorders in healthy adolescents and
young adults.
The European Union and the Europen Social Fund has provided
financial support under the grant agreement No.: TAMOP 4.2.1./B-
09/1/KMR-2010-0003.
The study was co-funded by National Grants: OTKA F-46788 and
KAB-KT-10-0016

PP193 GENETIC VARIATION, ADHD SYMPTOMS, AND
SMOKING PHENOTYPES: A PRELIMINARY STUDY
L. Bidwell*(1), M. Garrett(1), F. McClernon(1), B. Fuemmeler(1),
R. Williams(1), A. Ashley-Koch(1), S. Kollins(1)
1. Brown University 2. Duke University Medical Center
*cinnamon_bidwell@brown.edu
Introduction: Symptoms of attention-deficit hyperactivity disorder
(ADHD) are a significant risk factor for smoking behaviors,
including earlier age of initiation and likelihood of progression to
regular use. Several converging lines of work suggest that the high
rates of smoking in the presence of ADHD symptoms may be related
to common genetic vulnerabilities that increase risk for both nicotine
dependence and ADHD. Therefore, it may be informative to include
ADHD symptoms in genetic studies of smoking. We conducted an
exploratory study to assess whether ADHD symptoms interact with
genetic variation to predict smoking phenotypes in a large
epidemiological sample.
Methodology: Participants were a subsample of 1,900 unrelated
individuals with genotype data drawn from the National Longitudinal
Study of Adolescent Health (Add Health), a nationally representative
sample of adolescents followed from 1995 to 2002. Linear
regression was used to examine relationships among self-reported
ADHD symptoms, genotype, and smoking phenotypes, including
self-reported initial reactions to cigarettes and lifetime history of
regular smoking.
Results: No main effect for any of these polymorphisms was
observed in predicting smoking phenotypes. DRD2 and MAOA
polymorphisms both interacted with ADHD symptoms to
significantly predict early smoking experiences and risk for lifetime
smoking. Interactions with ADHD symptoms and SLC6A4, DRD4,
andCYP2A6 genes in predicting smoking phenotypes were also
found.
Conclusions: These findings, while preliminary, suggest that
genotypes associated with dopamine neurotransmission and nicotine
metabolism interact with ADHD symptoms to influence early and
later smoking risk. Theseresults suggest that ADHD symptoms
qualify genetic associations with smoking phenotypes in important
ways and should be accounted for in genetic studies of smoking.
167

POSTER SESSION IV
ABSTRACTS
168

STATISTICAL GENETICS, GENETIC
EPIDEMIOLOGY
PP194 GENOME-WIDE INTERACTION ANALYSIS IN A
DANISH POPULATION-BASED SCHIZOPHRENIA SAMPLE
ECIP
L. Foldager*(1,2), J. Grove(2,3), D. Demontis(3), M. Hollegaard(4),
T. Ørntoft(5,6), M. Didriksen(7), D. Hougaard(4), C. Wiuf(2), P.
Mortensen(8), O. Mors(1), A. Børglum(1,3)
1. Centre for Psychiatric Research, Aarhus University Hospital 2.
Bioinformatics Research Centre, Aarhus University 3. Inst. of
Biomedicine, Dept. of Human Genetics, Aarhus University 4. Section
of Neonatal Screening and Hormones, Dept. Clinical Biochemistry
and Immunology, Statens Serum Institut 5. Dept. of Molecular
Medicine, Aarhus University Hospital 6. AROS Applied
Biotechnology A/S 7. Synaptic transmission, H. Lundbeck A/S 8.
National Centre for Register-based Research, Aarhus University
*leslfold@rm.dk
Introduction: In a search for single nucleotide polymorphism (SNP)
interactions in a Danish genome-wide association study of
schizophrenia (SZ) we applied a number of genome-wide interaction
strategies. The aim was to 1) complement the single-marker analysis,
2) pursue interesting pathways, and 3) compare various interaction
analysis methods.
Methodology: The case sample consisted of Danish citizens born in
May 1981 or later who had a diagnosis of SZ (ICD-10 F20) in the
Danish registries as of May 2007. One-to-one matched controls were
selected as follows: same birth date, same gender, not the same
mother, resident in Denmark (and alive) and without a registered
diagnosis of SZ at the time of the first SZ diagnosis of the case. DNA
was extracted using whole-genome-amplification from neonatal dried
blood spot samples obtained from the Danish Newborn Screening
Biobank and genotyped using the Illumina Infinium HD Human610-
Quad BeadChip. Quality control (QC) excluded subjects having a call
rate less than 0.97, and SNPs with call rate less than 0.99, minor
allele frequency less than 0.0015 or Hardy-Weinberg equilibrium P
value less than 0.0001. A total of 869 schizophrenia cases (397
females and 472 males) and an equivalent number of matched
controls remained for the analyses. We only consider SNPs from
autosomes in which a total of 527,833 SNPs remained after QC.
Single-marker additive analysis (trend test) and test for additive
interaction between pairs of markers were carried out with
conditional logistic regression using Stata. Population stratification
was accounted for by inclusion of the first principal component
obtained by Eigenstrat on a pruned subset of 42,388 autosomal SNPs
not in linkage disequilibrium (r2

PP196 MATHEMATICALLY-BASED INTEGRATION OF
MULTIPLE HETEROGENEOUS GENETIC DATA SETS
J. Bukszar*(1), A. Khachane(1), K. Aberg(1), Y. Liu(2), J.
McClay(1), P. Sullivan(2), E. van den Oord(1)
1. Center for Biomarker Research and Personalized Medicine, School
of Pharmacy, Virginia Commonwealth University 2. Department of
Genetics, University of North Carolina at Chapel Hill
*jbukszar@vcu.edu
Introduction: We present MIND, a novel mathematically-based
framework/software that integrates information from multiple
heterogeneous existing data sets into a novel data collection in order
to identify markers associated with a complex disease. MIND can
integrate existing data sets generated by any kind of technology (e.g.,
expression arrays, proteomics, GWAS) or activity (e.g., actual data
collection, literature search, construction of disease-specific
biochemical networks). Furthermore, external data may provide
information at any genetic level ranging from individual variants
(e.g., SNPs), genes (e.g., literature search), groups of genes (e.g.,
pathways), or entire chromosomal segments (e.g., linkage studies or
targeted next-generation sequencing). A unique feature of MIND is
that it is entirely based on a solid mathematical foundation, which
ensures substantially higher accuracy than widely used heuristic
methods.
Methodology: First, we developed the mathematical formulas that
provide us with the exact posterior probability that a marker is
associated with a certain disease based on the information in different
type of data sets. We then formulated a parametrization that allowed
us to collapse many model parameters into a single parameter, for
which we developed a precise estimator. We implemented the
method in a freely-available and user-friendly R package, called
MIND (Mathematically-based Integration of heterogeNeous Data).
Moreover, we developed tools that assess whether an existing data set
is informative or not, and tools that allow us to measure the increase
in total information by adding a new data set.
Results: Through simulations and cross-validation analyses
involving GWAS meta-analyses of psychiatric disorders as well as an
actual replication study of over 6,500 SNPs in 6,300 schizophrenic
patients and their family members we show that MIND 1) is accurate,
2) outperforms marker selection for follow up studies based on pvalues,
and 3) identifies effects that would otherwise require
replication of over 20 times as many markers.
Conclusions: MIND is able to make use of the multi-dimensional
data that is become available from the dramatically growing
repositories and other data bases to detect effects that would
otherwise require prohibitive large sample sizes or replication
studies.
170
PP197 EVIDENCE FOR ASSOCIATION OF PRO-
INFLAMMATORY CYTOKINE GENE
POLYMORPHISMS WITH SCHIZOPHRENIA IN SOUTH
INDIAN POPULATION
L. Srinivas*(1), N. V.(1), C. Nair(2), P. Allencherry(3), M.
Banerjee(1)
1. Human Molecular Genetics Laboratory, Rajiv Gandhi Centre for
Biotechnology 2. Nair's Hospital 3. Mental Health Centre
*lekshmys@gmail.com
Introduction: Schizophrenia is a severe and debilitating mental
disorder with a lifetime risk of about 1%, characterized by
hallucinations, delusions and cognitive deficits, with heritability
estimated at up to 80%. It is a complex disorder which may involve
multiple genes with mild to moderate effect and non-genetic risk
factors like environmental and psychological assaults. Cytokines,
regulators of immune/inflammatory reactions and brain development,
emerge as part of a common pathway of genetic and environmental
components of schizophrenia. They are secreted by various cells and
act as signals between cells to regulate the immune response to injury
and infection. In addition to providing communication between
immune cells, specific cytokines play a role in signaling the brain to
produce neurochemical, neuroendocrine, neuroimmune, and
behavioral changes. They strongly influence the dopaminergic,
noradrenergic, and serotonergic neurotransmission. Considering these
factors, cytokines are implicated as a contributing factor for
schizophrenia. Functional polymorphisms in cytokine genes may
predispose individuals to schizophrenia. Genome-wide association
studies in schizophrenia have found significant associations with
several single nucleotide polymorphisms (SNPs) across the major
histocompatibility complex (MHC) region reinforcing an immune
component to schizophrenia risk.
Methodology: We performed a case-control association study using
248 patients from Kerala, South India and 244 normal healthy
ethnically matched controls. We screened 23 SNPs and 1 VNTR
polymorphism from 10 cytokine genes (IL1A, IL1B, IL1RN, IL3,
IL4, IL6, IL10, IFNG, TNFA and TGFB1). Genomic DNA was
isolated from subjects and genotyping was carried out by PCR-RFLP,
Taqman allelic discrimination assay and Kaspar assays. Data analysis
including allelic, genotypic, haplotypic and diplotypic frequencies
were calculated and compared using Unphased v3.0.13 software. LD
between SNPs was also computed using Unphased. Hardy Weinberg
equilibrium (HWE) was calculated and LD plots were generated
using Haploview v4.1.
Results: Functional polymorphisms in pro-inflammatory cytokine
genes IL1A, IL6, TNFA and IFNG were found to be associated with
schizophrenia. IL1A polymorphism -889G/A (rs1800587) was found
to be associated with schizophrenia at the allelic (p= 0.0269),
genotypic (p=0.0412), haplotypic and diplotypic levels. IL6 -572 G/C
(rs1800796) was found to be associated with the disease at the
genotypic (p=0.0038) and at the diplotypic level (p=0.001). IL6 -174
G/C (rs1800795) was found to be associated at the allelic (p=0.0374),
genotypic (p=0.0339), haplotypic (p=0.02) and diplotypic levels
(p=0.001). TNFA -238G/A (rs361525) polymorphism was also
significantly associated (allelic p=0.0216, genotypic p=0.0063).
Statistically significant association was also observed with IFNG
+3232 C/T (rs2069718) at the genotypic level (P= 0.0096). We also
found a very strong protective effect of this polymorphism at the
haplotypic (p=9.23E-07) and diplotypic (p=1.51E-07) levels.
Significant differences were observed between the LD plots of IL-6
and IFNG in cases and controls.
Conclusions: Our findings of association of cytokine gene
polymorphisms with schizophrenia support the hypothesis that
genetically determined changes in cytokine regulation may contribute
to the pathogenesis of schizophrenia confirming a role of immune
genes in disease susceptibility

PP198 D-AMINO ACID OXIDASE ACTIVATOR GENE
(DAOA) VARIATION AFFECTS CEREBROSPINAL FLUID
HOMOVANILLIC ACID CONCENTRATION IN HEALTHY
CAUCASIANS
D. Andreou*(1), P. Saetre(1), T. Werge(2), O. Andreassen(3,4), I.
Agartz (1,5,6), G. Sedvall(1), H. Hall(1,7), L. Terenius(1), E.
Jönsson(1)
1. Department of Clinical Neuroscience, HUBIN project, Karolinska
Institutet and Hospital, R5:00, SE-171 76 2. Research Institute of
Biological Psychiatry, Mental Health Center Sct. Hans, Copenhagen
University Hospital 3. TOP project, Division of Psychiatry, Ullevål
University Hospital, University of Oslo 4. TOP project, Institute of
Clinical Medicine, Psychiatry section Vinderen, University of Oslo 5.
Department of Psychiatry, Diakonhjemmet Hospital 6. Institute of
Psychiatry, University of Oslo 7. Department of Public Health and
Caring Sciences, Uppsala University
*dimitrios.andreou@sll.se
Introduction: Variation in the D-amino acid oxidase activator gene
(DAOA) has been associated with schizophrenia, schizophreniarelated
characteristics, major depression and bipolar disorder. The
DAOA protein has been detected in various parts of the central
nervous system and modulates the function of D-amino oxidase
(DAO), an enzyme that catalyzes the oxidative deamination of Dserine
and D-3,4-dihydroxyphenylalanine (D-DOPA). D-serine is
implicated in glutamatergic transmission, whereas D-DOPA is
converted to L-3,4-DOPA, a precursor of dopamine and
noradrenaline. We hypothesized that DAOA polymorphisms are
associated with dopamine, serotonin and noradrenaline turnover in
the human brain.
Methodology: Unrelated healthy Caucasian participants (n=132)
were included in the study. Genomic DNA was extracted from whole
blood samples and four single nucleotide polymorphisms (rs2391191,
rs778294, rs3918342, rs1421292) previously reported to be
associated with schizophrenia,were genotyped using the Illumina
Bead Station 500GX and the 1536-plex Illumina Golden Gate assay.
Cerebrospinal fluid (CSF) samples were drawn by lumbar puncture
and the concentrations of the major dopamine metabolite
homovanillic acid (HVA), the major serotonin metabolite 5hydroxyindoleacetic
acid (5-HIAA), and the major noradrenaline
metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) were
measured with mass fragmentography. To test allele association
between DAOA SNPs and CSF monoamine metabolite
concentrations, each monoamine metabolite was analyzed with a
general linear model where the concentration was modeled as a linear
function of the allele count of each SNP separately and one or more
covariates
Results: Two of the investigated DAOA polymorphisms, rs3918342
(corrected p-value=0.013) and rs1421292 (corrected p-value=0.043),
were found to be significantly associated with CSF HVA
concentrations. Rs1421292 was nominally associated with CSF 5-
HIAA concentrations. None of the SNPs were associated with MHPG
concentrations. Rs3918342 and rs1421292 were in strong linkage
disequilibrium with each other and no additional effect of rs1421292
on HVA concentration, on top of rs3918342, was observed. Carriers
of the rs3918342 T allele had 50 nmol/l lower HVA mean
concentration compared to C homozygotes.
Conclusions: Two DAOA polymorphisms, likely to capture the same
signal, were significantly associated with CSF HVA concentrations,
indicating altered dopamine turnover in healthy human subjects. This
association may indirectly explain the replicated effect of DAOA on
human behavior and psychiatric symptomatology. Further research is
needed in order to reveal whether the association between DAOA and
the dopamine system is also present in patients with schizophrenia
and other psychiatric disorders.
171
PP199 ROBUST CALLING OF RARE AND POTENTIALLY
COMMON CNVS IN SPECIFIC GENOMIC REGIONS
D. Ivanov*, E. Rees, M. O'Donovan, M. Owen, G. Kirov
Cardiff University
*ivanovdk2@cf.ac.uk
Introduction: Copy number variants (CNVs) account for a relatively
large proportion of the human genetic variation and have been
implicated as risk factors for common and rare disorders (Craddock,
Hurles et al. 2010). Successfully identifying genuine CNVs is a nontrivial
task (Baker 2010 Craddock, Hurles et al. 2010). Several
methods have been proposed to normalize data and reduce interindividual
variation, although no single method works for every CNV
(Craddock, Hurles et al. 2010 Dellinger, Saw et al. 2010). Here we
propose an improved analytical approach for calling of CNVs with a
relatively high degree of confidence.
Methodology: The method consists of genome-wide normalization
of inter-individual variation, by using normalized intensity ratios (i.e.
Log 2 Ratio derived from SNP arrays), followed by a genome-wide
normalization of individual inter-probe variation. The method is an
extension of the MeZOD method, by McCarthy et al (McCarthy,
Makarov et al. 2009). Median z-scores for specific regions of interest
were subsequently used to produce intensity histograms, where
outliers represent potential CNVs. Although the method relies on
calculating median z-scores for specific regions of interest, unlimited
number of regions could be examined using the same normalized
data. Furthermore, an automatic approach of CNV calling could be
utilized by the use of normalized median z-scores.
Results: The method was successfully used to identify schizophrenia
CNV loci in 662 affected proband-parent trios. 270 CNVs were
tested for validation with Agilent aCGH custom arrays. A
conservative approach in calling CNVs with the z-score method
resulted in 2.4% false positives and 5% false negatives, whereas a
non-conservative approach produced 7.7% and 1.9% false positive
and false negative rates respectively.
Conclusions: We conclude that this method allows users to make
highly confident predictions for the validity of any CNV, called by
different CNV-calling algorithms, or for specific regions of interest.
Programs for using this method are freely available at:
http://x004.psycm.uwcm.ac.uk/~dobril/z_scores_cnvs/

PP200 THE IMPACT OF THE PHENOTYPIC
HETEROGENEITY ON GENOME-WIDE ASSOCIATION
STUDIES IN COMPLEX PSYCHIATRIC DISEASES: A
SIMULATION CASE-CONTROL STUDY
M. Manchia*, J. Cullis, M. Alda
Department of Psychiatry, Dalhousie University 5909 Veterans'
Memorial Lane Room 3089, A.J. Lane Bldg, B3H 2E2
*mirko.manchia@dal.ca
Introduction: Findings from genome wide association studies
(GWAS) of psychiatric disorders have identified genetic risk variants
that explain only a fraction of the total phenotypic variance.
Researchers have hypothesized that part of the missing heritability of
complex diseases could be attributed to yet undetected rare risk
variants with larger effect sizes than common variants. Another
possible explanation is that of phenotypic heterogeneity affecting
GWAS findings. Psychiatric diseases are characterized by clinical
heterogeneity that can influence the accuracy of phenotyping in
genetic studies. For instance, imprecise phenotyping can reduce the
estimate of the effect sizes of the associated variants. In bipolar
disorder (BD), researchers have attempted to reduce clinical
heterogeneity by using subphenotypes such as early-onset BD,
presence of mood incongruent psychosis, or response to lithium
treatment. Increased homogeneity of such group of patients can
improve statistical power of detecting true association signals in
genetic studies.
Methodology: To study the impact of phenotypic heterogeneity on
GWAS findings, we simulated case-control data assuming increasing
(up to 90%) phenotypic admixture (β) in cases. For each level of
admixture, we calculated the minimum sample size needed to achieve
90% of the statistical power requested to detect association signals at
P < 5 x 10 -8 . Simulations were performed testing different genotype
relative risks (GRRs) (1.1, 1.2, 1.3, 1.5, 2, 5), for varying population
prevalence (F = 0.001, 0.01, 0.05, 0.1), under dominant and
multiplicative genetic models using a compiled script run in R
environment.
Results: Admixture significantly affected the sample size required to
reach a power of 90% for significant threshold set at P < 5 x 10 -8 . We
observed that: 1) heterogeneity caused a significant loss of statistical
power that was disproportionately larger than the admixture: increase
in a proportion of “non-cases” resulted in a non-linear increase of the
sample size needed to achieve 90% of statistical power. For instance,
admixture set at 50% required at a minimum three times the sample
size needed to achieve the same statistical power without admixture
2) heterogeneity caused a marked reduction of the estimated effect
size reflected in decrease of estimated odds ratios. This effect size
reduction was also non-linear in relation to the degree of admixture.
Conclusions: These findings from a simulated case-control study
provide evidence on the impact that phenotypic heterogeneity can
exert on GWAS findings. The absence of admixture ensures the need
of significantly smaller sample sizes to achieve the same statistical
power of larger sample sizes with medium-high level of phenotypic
heterogeneity. The accuracy in the phenotypic assessment and the use
of subgroups such as responders to lithium treatment in BD can
significantly decrease the number of cases needed to be collected in
order to achieve sufficient statistical power to detect association
signals in GWAS.
172
PP201 FAMILY-BASED ASSOCIATION ANALYSIS OF
GENES INVOLVED IN SYNAPTIC PLASTICITY AND
AUTISM
R. Sasanfar*(1,2,), R. Siburian(2), M. Ghadami(3), S. Haddad(2), A.
Tolouei(4), B. Galloway(2), M. Rostami(5), S. Chang(6), A.
Mahmoodizadeh(4), S. Santangelo(1,2,6)
1. Harvard Medical School 2. Massachusetts General Hospital 3.
Research Institute for Education 4. Special Education Organization 5.
Kariminejad-Najmabadi Pathology & Genetics Center 6. Harvard
School of Public Health
*rsasanfar@pngu.mgh.harvard.edu
Introduction: A wide variety of evidence, using many different
behavioral paradigms, indicates a broad role for the involvement of
the extracellular signaling-regulated kinases (ERK) pathway in
synaptic plasticity and consequently learning and memory.
Disruption of neuronal protein synthesis through ERK pathway is the
shared point of several essential pathways associated with autism
including the mTOR pathway. Therefore, aberrant regulation of the
ERK pathway is a potential cause for deficits associated with autism.
Methodology: Family-based association analysis was performed
using 700 individuals from 200 nuclear families from Iran with at
least one autistic child. In total, 175 SNPs were genotyped for all six
genes using Sequenom iPLEX. TDT analyses were performed with
Plink software. Quality control procedures applied to the data
included rejection of any SNP markers with missingness greater than
0.15, MAF less than 0.01, HWE p-value less than 2.8*10 -4 , and
Mendelian Error rate of greater than 0.1. Families with a Mendelian
Error rate of greater than 0.05 were also removed. After QC, 150
SNPs and 672 individuals from 194 nuclear families were analyzed.
Results: We failed to identify a significant association with these six
genes and ASD. The best result was a nominally significant
association of two markers from GRM1(rs9403771, p=.047, and
rs2024589, p=.049) and one marker from GRIN2A (rs11645219,
p=.046). Analysis is ongoing using Plink and FBAT to explore
potential multimarker associations and gender effects.
Conclusions: Although the sample size for this investigation is small
and slightly underpowered (For a significance level of 0.05, there is
78% power to detect a heterozygote GRR of 2.0 at D’ = 0.8 for q =
0.1), our results do not support the involvement of these genes in
conferring risk for ASD.

PP202 HOW IS MET/MET GENOTYPE OF THE
CATECHOL-O-METHYL-TRANSFERASE VAL 108/158 MET
POLYMORPHISM ASSOCIATED WITH SUICIDE VICTIMS
FROM SLOVENIA?
A. Videtič Paska*(1), P. Pregelj(2), M. Nikolac(3), T. Zupanc(4), G.
Nedic(3), D. Muck Seler(3), R. Komel(1), N. Pivac(3)
1. Institute of Biochemistry, Faculty of Medicine, University of
Ljubljana 2. University Psychiatric Hospital Ljubljana 3. Laboratory
for Molecular Neuropsychiatry, Division of Molecular Medicine,
Rudjer Boskovic Institute 4. Institute of Forensic Medicine, Faculty
of Medicine, University of Ljubljana
*alja.videtic@mf.uni-lj.si
Introduction: Slovenia is one of the countries with the highest
suicide rate in the world. In the year 2007 suicide rate was 21.5
suicide victims per 100.000 citizens. So far, the results from the
association studies of the various candidate genes for suicide are
contradictory, with a lot of either positive associations or lack of
associations. The most of the studies suggest the implication of
specific signaling pathways, like serotonergic or catecholaminergic
pathway, in suicide. ΦAmong the later the genes for dopaminergic
receptors DRD2 and DRD4, dopamine transporter, dopamine-betahydroxylase,
DOPA decarboxylase, aromatic L amino acid
decarboxylase and catechol-o-methyl-transferase (COMT), are
frequently studied candidate genes for suicide. It was hypothesized
that COMT Val 108/158 Met polymorphism is associated with suicide,
independently of psychiatric disorders. COMT is an enzyme that
inactivates catecholamines (dopamine, norepinephrine and
epinephrine) by thetransfer of a methyl group which leads to
degradation of the molecule. A functional polymorphism on the
COMT gene, COMT Val 108/158 Met,a G to A nucleotide transition
resulting in valine (Val) to methionine (Met) substitution, was
associated with psychiatric disorders related to high suicide risk and
to suicidal behavior.
Methodology: In a study comprising of 356 samples from suicide
victims and 198 samples from control non-suicidal victims who died
from traffic accidents, COMT Val 108/158 Met polymorphism was
evaluated. To our knowledge we were the first to test the association
of completed suicide and COMT Val 108/158 Met polymorphism
hypothesis on Caucasian population.
Results: The results revealed significant differences in the
frequencies of the COMT Val 108/158 Met variants in male and female
suicide victims and male and female control groups. There were
significant differences in the frequencies of the Val/Val, Val/Met and
Met/Met genotypes, Val and Met alleles, or Val carriers and the
homozygous Met/Met genotype between male control and male
suicide victims, or male control and male violent suicide victims. On
the other hand, there was no significant difference in the frequency of
COMT Val 108/158 Met variants between female control and female
suicide victims. Male carriers of the Met/Met genotype were detected
more frequently in male control, than in male suicide victims.
Conclusions: Our results, obtained on the sample from homogenous
unrelated Caucasians, originating from Slovenia, suggest that suicide
victims were less frequently carriers of the Met/Met genotype than
control subjects, and that Met/Met genotype of the COMT
Val 108/158 Met might have a protective role against suicide. However,
we are suggesting further studies in order to confirm our results.
173
PP203 MENTAL HEALTH, GENDER AND SIBLING
FERTILITY
R. Power*(1), P. Lichtenstein(2), P. McGuffin(1), C. Lewis(1), A.
Svensson(2)
1. Institute of Psychiatry 2. Karolinska Institutet
*robert.r.power@kcl.ac.uk
Introduction: The combination of high heritability, high prevalence
and a large decrease in fecundity compared to the general population
means psychiatric disorders should face strong purifying selection.
However almost every psychiatric disorder is sexually dimorphic and
so will be exposed to sexual selection. Since fecundity is reduced, it
is clear that negative health in the individual is not outweighed by
increased ability to attract mates or have children. However selection
may affect the frequency of sexually antagonistic genes, those that
increase the fitness of one sex at the expense of the other. To give a
possible example, autism (found more commonly in males) might
result from the burden of several female beneficial alleles. This
would lead to balancing selection on these genetic variants, keeping
them at a stable frequency in the population.
Methodology: Using the Swedish Multi-Generation Register and
Hospital Discharge Register we examined evidence for sexually
antagonistic genes in 4 psychiatric disorders. Fertility of affected
individuals and their siblings was calculated as a ratio to that of the
general population. The hypothesis being that individuals with
disorders common in males should have sisters with increased fitness
and brothers with decreased fitness, with the opposite being true for
those disorders common in females. We chose anorexia nervosa and
depression as female biased disorders (M:F ratios of 1:10 and 1:2
respectively), and substance abuse and autism as male biased
disorders (both 4:1). We combined previously explored inpatient
records from 1973 to 2009 with outpatient records from 2001. A birth
cohort including all individuals born between 1950 and 1980 was
selected, to balance inclusion in all aspects of the dataset, diagnostic
reliability, and likelihood of completing reproductive cycle. The total
cohort included 4.4 million individuals, and ICD codes were used to
identify affected individuals and their siblings.
Results: Anorexia nervosa had a prevalence of 0.12% and sibling
frequency of 0.17%. Depression had a prevalence of 3.44% and
sibling frequency of 4.5%. Autism had a prevalence of 0.26% and a
sibling frequency of 0.35%. Substance abuse, including alcoholism,
had a prevalence of 1.74% and a sibling frequency of 2.39%. Using
generalized estimating equations to account for within family
correlation and year of birth, a fertility ratio of affected individuals
and their siblings compared to the general population was calculated.
In the four disorders the fertility of affected individuals varied but
always differs from the general population significantly: a ratio of
1.01 for depression compared to general population was found 0.61
for anorexia 0.79 for substance abuse and 0.29 for autism. For
siblings there was a general trend, with brothers' having consistently
significantly lower fertility than the general population (0.77-0.95)
and sisters having significantly increased fertility (1.14-1.27).
Conclusions: This similar trend across all disorders, whether more
common in males or females, was not what we expected to find in the
presence of sexually antagonistic genes. For several of these
disorders we believe these to be the first results on the impact on
siblings' fertility, and while we have yet to fully explore the cause it
is clear that sex seems to play a crucial role in the direction of effect.
Better understanding of the differential effects of the genes for
psychiatric disorders will hopefully lead to a better understanding of
the genetic architecture of these disorders and the identification of the
causal variants.

PP204 STRONG STABILITY IN GENETIC INFLUENCES ON
AUTISTIC TRAITS IN CHILDHOOD: A LONGITUDINAL
STUDY OF MORE THAN 6000 TWIN PAIRS
K. Holmboe*(1), V. Hallett(1), F. Happé(1), R. Plomin(1), A.
Ronald(2)
1. MRC Social, Genetic and Developmental Psychiatry Centre,
Institute of Psychiatry, King's College London 2. Department of
Psychological Sciences, Birkbeck, University of London
*karla.holmboe@gmail.com
Introduction: Autism spectrum disorders (ASDs) constitute a set of
developmental disorders characterized by deficits in the three core
domains of social interaction, communication, and restricted,
repetitive and stereotyped behaviors and interests. Sub-clinical
autistic traits are detectable and show quantitative variation in the
general population. Previous studies have found autistic traits in the
general population to be moderately to highly heritable and to show
modest environmental influences from infancy to early adulthood.
However, it is not known whether the genetic and environmental
influences on autistic traits that are important at one age are the same
as at other ages. Answering this question is important in order to
understand the developmental course of autistic traits and the causal
influences that determine this course. The present study is the first
population-based twin study to investigate the question of causal
influences on the longitudinal development of autistic traits across
middle childhood.
Methodology: The sample included 6,280 twin pairs from the Twins
Early Development Study (a United Kingdom general population
study). Male and female twins were assessed on the same measure of
autistic traits (CAST: Childhood Asperger Syndrome Test; Scott,
Baron-Cohen, Bolton, & Brayne, 2002) by teachers at ages 9 and 12
years, and by parents at ages 8, 9 and 12 years. Data were subjected
to structural equation modeling, and parameter estimates were
derived from the best-fitting model. A Cholesky decomposition
model was employed.
Results: The parent data indicated high stability of autistic traits
between ages 8, 9 and 12 for both males and females (r = .57-.67),
whereas stability was more modest in the teacher data (r = .25-.35).
The best-fitting model for the parent data involved additive genetic
influences (A), reflecting the additive effect of alleles influencing
autistic traits; nonadditive genetic influences (D), reflecting
interactions between alleles at the same locus; and nonshared
environmental influences (E), which impact on each individual and
also include measurement error. The best-fitting model for the
teacher data also included A and E, and a modest shared environment
component (C), reflecting environmental influences that make
children growing up in the same family similar. High heritability was
observed in the parent data. There was also some difference between
sexes, with males showing nonadditive genetic effects, which females
did not. Teacher ratings showed moderate heritability and nonshared
environmental influences and small effects of the shared
environment. The longitudinal modeling revealed high genetic
correlations, suggesting substantial stability in the genetic influences
on autistic traits between 8 and 12 years of age.
Conclusions: In conclusion, it is well known that ASDs are highly
heritable and that diagnoses tend to be stable across the life span.
Here we present the first evidence from a longitudinal populationbased
twin study demonstrating that individual differences in autistic
traits in the general population are also stable and highly heritable,
and that this stability is due, in large part, to similar genetic
influences operating across middle childhood.
174
PP205 EEG WAVE PATTERNS IN BIPOLAR DISORDER
AND SCHIZOPHRENIA: COMPUTATIONAL
DISCRIMINATION DURING GO/NOGO PARADIGMS
Z. Syed*(1), M. Kamali(1), P. Deldin(1), L. O'Donnell(1), J.
Chun(2), M. McInnis(1)
1. University of Michigan 2. Harvard University
*zhs@umich.edu
Introduction: Bipolar disorder (BD) and schizophrenia (SZ) have
considerable overlapping features and are characterized by deficits in
response inhibition and social cognition relative to controls (CT). We
explored the ability of sophisticated computational models using L1regularized
L2-loss support vector machine (SVM) classification of
emotional Go/NoGo P300 peak amplitudes to distinguish between
SZ, BD and CT patients.
Methodology: 25 BD, 19 SZ and 20 CT patients were presented with
a target (Go) or distractor (NoGo) emotion. In half the blocks one
type of emotional face (angry, sad, happy) served as target while
neutral faces were distractors. In the other half of the blocks the roles
of targets and distracters were reversed. A total of 12 blocks with 600
trials took about 20-25 minutes. Neurophysiological testing was
completed while measuring electroencephalograhy (EEG) and eventrelated
brain potentials were obtained from the EEG data. For each
pair of categories out of BD, SZ and CT, a separate L1-regularized
L2-loss SVM was trained and evaluated using leave-one-out crossvalidation
on the average peak P300 amplitudes across all laterality x
caudality x blocks (3 x 3 x 12 = 108 features). SVM parameters were
learned by further cross-validation within the data in each iteration
excluding the held out set.
Results: L1-regularized L2-loss SVM classification of peak P300
amplitudes produced a highly accurate diagnosis of SZ vs. CT [area
under the receiver operating characteristic curve (AUROC): 0.984,
precision: 94.7%, recall: 90.0%] and SZ vs. BP [AUROC: 0.983,
precision: 92.3%, recall: 96.0%]. The SVM-based approach achieved
moderate accuracy for the BP vs. CT case [AUROC: 0.720,
precision: 72.7%, recall: 64.0%].
Conclusions: Computational diagnostic models using emotion
modulated event-related brain potentials can form the basis of
accurate discrimination between BP, SZ, and CT patients. These
models can generalize to unseen test data not used in model
development, and characterize differences between psychiatric
patients and controls, as well as between different forms of
psychiatric disease. There are considerable implications for genetics
research in characterizing the distinction between bipolar disorder
and schizophrenia.

PP206 DEPRESSION AND THE VAL66MET
POLYMORPHISM INFLUENCE THE SERUM BDNF LEVEL
H. Buttenschøn*(1), B. Elfving(1), L. Foldager(1,2), P. Poulsen(1),
J. Andersen(3), J. Bonde(4), M. Grynderup(5), A. Hansen(6), H.
Kolstad(5), A. Kærgaard(3), L. Kærlev(5,7), S. Mikkelsen(4), J.
Thomsen(4), A. Børglum(1,8), G. Wegener(1), O. Mors(1)
1. Centre for Psychiatric Research, Aarhus University Hospital,
Risskov 2. Bioinformatics Research Centre, Aarhus University 3.
Danish Ramazzini Center, Department of Occupational Medicine,
Regional Hospital 4. Department of Occupational Medicine,
Bispebjerg University Hospital 5. Danish Ramazzini Center,
Department of Occupational Medicine, Aarhus University Hospital 6.
National Research Centre for the Work Environment 7. Center for
National Clinical Databases South, Odense University Hospital 8.
Institute of Biomedicine, Dept of Human Genetics, Aarhus
University
*henrbutt@email.dk
Introduction: Depression may involve neurodegeneration and
aberrant neuronal network function. One of the most extensively
investigated targets with respect to brain neuroplasticity is brainderived
neurotrophic factor (BDNF). Several studies have reported a
difference in plasma and serum level of BDNF for individuals with
depression and healthy controls. BDNF has been suggested as a
candidate gene for depression.
Methodology: The purpose of the present study was to perform a
thorough investigation of BDNF using 163 individuals with
depression and 290 healthy individuals. All individuals returned a
completed questionnaire and participated in a semi-structured
diagnostic interview. We included socio-demographic variables and
health indicators. We determined serum BDNF levels and
successfully analyzed six SNPs for association with depression. To
assess independent determinants of BDNF we applied multiple linear
regression models.
Results: Several variables were correlated with the serum BDNF
level. Age at diagnostic interview was the most significantly
associated variable. We also observed a significant difference in
serum BDNF level between cases and controls. However, in contrast
to other studies we observed the BDNF level to be higher among
cases compared to controls. A significant interaction between sex and
the Val66Met polymorphism was furthermore observed. In the
genetic analyses none of the genotyped SNPs were associated with
depression.
Conclusions: We conclude that the serum BDNF level is influenced
by several factors including age, depression, the interaction between
sex, and Val66Met polymorphism.
175
PP207 EXPLORATION OF GENETIC RISK,
SCHIZOPHRENIA AND BRAIN VOLUME
G. Russo*(1), A. Vasquez(2,3), M. Rijpkema(4), G. Fernández(4,5),
H. Brunner(2), P. Holmans(1), B. Franke(2,3), O. Michael (1), O.
Michael(1)
1. MRC Centre fr Neuropsychiatric Genetics and Genomics 2.
Department of Human Genetics, Institute for Genetic and Metabolic
Disorders, Center for Neuroscience, Radboud University Nijmegen
Medical Center 3. Department of Psychiatry, Donders Institute for
Brain, Cognition and Behavior, Center for Neuroscience, Radboud
University Nijmegen Medical Center 4. Donders Institute for Brain,
Cognition and Behavior, Center for Cognitive Neuroimaging,
Radboud University Nijmegen 5. Department of Neurology, Donders
Institute for Brain, Cognition and Behavior, Center for Neuroscience,
Radboud University Nijmegen Medical Center
*russog@cf.ac.uk
Introduction: Whole and regional brain volumes and psychiatric
phenotypes have shared familial/genetic factors. The present study
investigates the relationship between common genetic risk factors for
schizophrenia and brain volumes based on a) the data from the
Schizophrenia Psychiatric Genome-Wide Association Study (GWAS)
Consortium (PGC) and b) the Brain Genetic Imaging (BIG) sample
of 926 healthy individuals for whom the brain volumes of 11 brain
regions have been measured via Magnetic Resonance Imaging
(MRI). Our aim was to test the hypothesis that single nucleotide
polymorphisms (SNPs) associated with the risk of SZ are also related
to the variance of the volumes of brain structures in healthy
individuals, and that the risk variants might consistently implicate the
same brain structure.
Methodology: We investigated the 10 independent, genome-wide
significant SNPs identified by the PGC. A correlation analysis based
on singular value decomposition of the matrix of the 11 brain
measures was performed to appropriately correct for multiple testing.
With this method, we retrieved 3 independent measures. A polygenic
score analysis was also performed to evaluate the cumulative effect
of large collections of SNPs enriched for risk alleles. For each brain
volume, alleles were selected from the BIG GWAS that surpassed a
range of arbitrary association thresholds (0.5, 0.1, 0.01, and 0.001)
and these were used to try to predict SZ state in a subset of the PGC
dataset.
Results: With 10 independent SNPs, there are 30 independent tests,
and an effective significance threshold of P = 0.0017. Before multiple
testing correction, four SNPs were nominally significantly associated
(p < 0.05) with at least one brain region, there being a total of 10
nominally significant findings. The most significant associations
were to rs11191580 at chromosome 10 which was associated with
reduced volume for 5 brain regions. Three of these signals remain
significant after correction for multiple testing (accumbens, P =
0.00076 globuspallidus, P = 0.00060 hippocampus, P = 0.0010). SNP
rs11191580 maps to NT5C2 (5'- nucleotidase, cytosolic II), but the
signal is not precisely located to this gene as a result of extensive LD
in the region. None of the other associations survived correction for
multiple testing. In the polygenic analyses, no prediction was
statistically significant after multiple testing correction, for which
permutations and singular value decomposition gave very similar
results.
Conclusions: Our study is consistent with the hypothesis that the
association between schizophrenia and rs11191580 may be mediated
through effects on brain development that are visible at the structural
level, although pleiotropy may be another explanation. We did not
find evidence that in general, the polygenic risk for schizophrenia is
shared with genetic variance in brain volumes. The size of our sample
might well be underpowered to detect such common genetic factors.
It is also possible that volumes as measured in this study are not the
best endophenotypes for the disorder, and that more consistent
evidence for shared genetic risk between schizophrenia and brain
structure will require more sophisticated analyses, for example
through hypothesis free voxel based morphometry, studies which are
currently under way.

PP208 FAMILIAL CLUSTERING OF SCHIZOPHRENIA,
BIPOLAR DISORDER AND MAJOR DEPRESSIVE
DISORDER
M. Aukes*(1,2), W. Laan(2), J. Buizer-Voskamp(1,3), F.
Termorshuizen(2), E. Hennekam(4), H. Smeets(2), R. Ophoff(1,3,5),
M. Boks(1,2), R. Kahn(1)
1. Rudolf Magnus Institute of Neuroscience, Department of
Psychiatry, University Medical Center Utrecht 2. Julius Center for
Health Sciences and Primary Care, University Medical Center
Utrecht 3. Department of Medical Genetics, University Medical
Center Utrecht 4. Department of Clinical Genetics, University
Medical Center Utrecht 5. Center for Neurobehavioral Genetics,
University of California
*m.aukes@umcutrecht.nl
Introduction: Recent population-based studies suggest that
schizophrenia and bipolar disorder share part of their genetic
vulnerability. Several molecular genetic studies have indeed
identified both shared and distinct genetic variants that are associated
with these disorders. Others suggest that a wide range of mental
disorders cluster in families. We investigated familial clustering of
schizophrenia, bipolar disorder, and major depressive disorder.
Methodology: By combining data from the Psychiatric Case Register
Middle Netherlands and Statistics Netherlands we obtained
information on 4,673 affected probands and 18,692 matched
population controls. We calculated the relative risks (RRs) for having
an affected sibling using the population matched group of controls as
a reference group.
Results: Probands with schizophrenia had relative risks for having a
sibling with schizophrenia of 3.50 (95% CI: 2.42–5.06), with bipolar
disorder of 1.46 (0.53-4.03) and with major depressive disorder of
(3.05, 2.47-3.77) compared to a reference proband. Probands affected
with bipolar disorder have a RR of 5.33 (2.15-13.22) for having a
sibling with bipolar disorder and of 1.59 (0.66-3.84) for having a
sibling with schizophrenia compared to a reference proband.
Probands affected with major depressive disorder also have increased
risk for having a sibling with schizophrenia (RR: 2.05, 1.56-2.69)
compared to a reference proband, which was similar to the risk for
having a sib with major depressive disorder (RR: 1.78, 1.52-2.09) or
bipolar disorder (RR: 1.89, 1.12-3.17).
Conclusions: Overall our findings are consistent with other large
population-based studies, in that they show the same decrease (about
twofold) for cross-wise schizophrenia-bipolar disorder risk compared
to within diagnoses risk. This reiterates the fact that although there
may be a shared familial vulnerabilitybetween schizophrenia and
bipolar disorder, risk is considerably lower across diagnostic entities.
However, for major depressive disorder risk was similar within and
across diagnostic entities. These data as well as previous reports are
consistent with a model in which there are underlying genetic or
environmental factors that give rise to broad, as well as specific,
familial vulnerabilities to psychiatric disorders.
176
PP209 T(9;17) (Q33.2;Q25.3) TRANSLOCATION REVEALS
THE ASSOCIATION BETWEEN BIPOLAR DISORDER AND
RNF213 AS WELL AS RPTOR GENES
ECIP
A. Rajkumar*(1,2), J. Christensen(1), I. Jacobsen(1), J. Pallesen(1),
D. Demontis(1), J. Grove(1), Z. Tümer(3), N. Tommerup(3), A.
McQuillin(4), H. Gurling(4), O. Mors(2), A. Borglum(1,2)
1. Department of Human Genetics, Aarhus University, 2. Center for
Psychiatric Research, Aarhus University hospital, Risskov 3.
Department of Cellular and Molecular Medicine, Copenhagen
University, 4. Department of Mental Health Sciences, University
College London,
*antoprajkumar@yahoo.com
Introduction: Rare copy number variants and other chromosomal
aberrations increase the risk for major psychotic disorders. Patients
with bipolar affective disorder (BD) and chromosomal aberrations
provide the impetus to investigate the association between BD and
the genes within those chromosomal breakpoint regions. Cross
linking Danish Psychiatric Case Registry and Danish Cytogenetic
Case Registry identified a patient with a t(917) (q33.2q25.3)
translocation and BD as well as alcohol dependence syndrome. We
aimed to identify the chromosomal breakpoint regions in that patient
and to investigate the association between BD and the single
nucleotide polymorphisms (SNPs) of known protein coding genes
within those regions in a larger population.
Methodology: We employed Fluorescent In Situ Hybridization
(FISH) to narrow down the breakpoint regions in that patient. We
used Ensembl and Biomart web tools to identify the genes within
those regions, which code for proteins, expressed in brain. We
accessed WTCCC, UCL and STEP-BD data and analyzed the allelic
and genotypic associations between BD and the SNP of those genes,
using Plink v1.07.
Results: We narrowed down 9q33.2and 17q25.3 breakpoint regions
within 112 KB (124,202,476-124,315,433) and 3l8 KB (78,267,202-
78,585,422) size, respectively. We identified three protein coding
genes (FLJ35220, RNF213 and RPTOR) in those regions. When we
analyzed the WTCCC data for the SNP of those genes, rs8072229,
rs4602089 and rs12601089 in RPTOR (Regulatory associated Protein
of MTOR, complex 1) had significant allelic and genotypic
associations with BD. When we analyzed WTCCC, UCL and STEP-
BD data together, rs7223701 and rs8359 in RNF213 (ring finger
protein 213) and rs4561525, rs11150864, rs8072229, rs4602089,
rs12601089, rs2138125, rs9911574 and rs7216306 in RPTOR were
significantly associated with BD (p < 0.05).
Conclusions: RPTORregulates cell growth and survival in response
to nutrient and hormonal signals. RPTOR and RNF213 may
contribute towards the complex etiology of BD. Further studies
investigating the underlying molecular pathways are desired.

PP210 KNOWN LIPID GENE VARIANTS CONSTITUTES A
MOLECULAR LINK BETWEEN REGULATION OF SLEEP
AND LIPID METABOLISM
H. Ollila*(1), S. Utge(1), E. Kronholm(2), T. Paunio(1,3)
1. Public Health Genomics Unit and Institute for Molecular Medicine
FIMM 2. Department of Chronic Disease Prevention, Population
Studies Unit, National Institute for Health and Welfare 3. Department
of Psychiatry, University of Helsinki
*hanna.m.ollila@helsinki.fi
Introduction: Epidemiological studies suggest a relationship
between lipid metabolism and regulation of sleep. In addition,
inactivation of circadian genes induces insulin resistance and
hyperlipidemia. We hypothesized that regulation of sleep length and
lipid metabolism is partially conducted by the same genes and aimed
to identify such genes in humans.
Methodology: We studied the association of total sleep time (TST)
with 60 genetic variants that had been previously associated with
lipid traits. The analyses were performed in a Finnish population
based sample comprising 6334 participants and replicated in 2189
twins. Finally, RNA expression from mononuclear leucocytes was
measured in 10 healthy volunteers before and after partial sleep
restriction (4 h sleep per night for 5 days).
Results: TST explained a small proportion of the variation in the
lipid traits. The genetic analysis identified variants near that
independently contributed to both blood lipid levels and to TST. The
strongest finding was replicated in twins. Meta-analysis further
strengthened the association and the association was not lost when
adjusted for lipid levels. RNA expression levels of the studied genes
were changed after the sleep restriction period in healthy individuals.
Conclusions: The results further support the connection between
sleep and lipid metabolism on genetic level. The shared genetic
background of these phenomena may at least partially explain the
well-established connection between diseases involving disrupted
metabolic processes such as cardiovascular disease, obesity and type
2-diabetes and sleep.
177
PP211 ASSOCIATION STUDY OF VESICULAR
MONOAMINE TRANSPORTER 1 (VMAT1) GENE WITH
BIPOLAR DISORDER IN A KOREAN POPULATION
Y. Kim *(1,2,3), J. Song(1,2), S. Kim (1,2), Y. Ahn (1,2,3)
1. Department of Psychiatry and Behavioral Science, Seoul National
University College of Medicine 2. Department of Neuropsychiatry,
Seoul National University Hospital 3. Institute of Human Behavioral
Medicine, Seoul National University College of Medicine
*kys@snu.ac.kr
Introduction: Vesicular monoamine transporters (VMATs) are
responsible for the uptake of cytosolic monoamines into synaptic
vesicles in monoaminergic neurons. Variations in the VMAT1 gene
might affect transporter function and/or expression of vesicular
monoamine transporters and might be involved in the etiology of
psychiatric disorders. The vesicular monoamine transporter 1 gene
(VMAT1/SLC18A1) maps to the shared bipolar
disorder/schizophrenia susceptibility locus on chromosome 8p21.
Methodology: We investigated the association of the SLC18A1,
which were suggested as potential susceptibility genes for bipolar
disorder. Along with 350 healthy individuals, 352 bipolar patients
were analyzed.
Results: All of the five examined single-nucleotide polymorphisms
(SNPs) of SLC18A1 (rs988713, rs2270641, rs2270637, rs1390938,
rs17092104) showed no significant association with bipolar disorder,
although rs988713 revealed a significant genotypic association with
bipolar disorder. However, the ‘‘C-G’’ haplotype of rs1390938 and
rs17092104 was overrrepresented in the patients with bipolar disorder
(P=0.019, OR=1.287), while the “G-G” haplotype was
underrepresented (P=0.03, OR=0.745).
Conclusions: These results support a possible role of the SLC18A1 in
bipolar disorder in Korean population. Further studies with larger
samples and phenotypes are necessary.

PP212 PORTRAIT OF SCHIZOPHRENIA IN PSYCHIATRIC
PATIENTS IN THE CITY OF MANAUS
A. Britto Junior*(1), H. Telles Ribeiro(2), L. Fajardo(3), A. Lima de
Souza(4)
1. Amazonas State University, School of Health Science 2.
Amazonas State University, Lab. of Genomics and Proteomics 3.
Amazonas State University, Eduardo Ribeiro Psychiatric Hospital 4.
Amazonas State University, Lab. of Human Genetics
*ademarbritto@gmail.com
Introduction: Schizophrenia (ESQ) is an intriguing psychiatric
illness, which has a prevalence of about 1% and generally affects
people during the height of their production processes.The ESQ, as
well as other complex diseases, seems to be caused by a number of
factors, including environmental and multifactorial inheritance.
According to the multifactor model, there are several genes involved
in this disorder that may act additively and suffer environmental
influences, increasing susceptibility to this disease and/or worsening
the patient's condition is a threshold genetic influenced by the
environment.
Methodology: Our research tryed to overview Manaus, the largest
city in northern Brazil, with approximately 2 million habitants. This
research is the first held in the Amazon that aims to study the genetic
patterns of this disease. Investigations were carried out in cases of
ESQ in the family of 17 diagnosed patients from the Eduardo Ribeiro
Psychiatric Center, through interviews with them, relatives or
guardians, which served as information for the pedigrees construction
for each family of the patients who agreed to participate.
Results: From the data analysis we made 17 families pedigrees,
containing 3-5 generations each, with 15-47 individuals in a total
universe of 463 people, 38 (23 men and 15 women) of those
diagnosed with schizophrenia.
Conclusions: The risk of developing schizophrenia was increased in
relatives of probands, and more pronounced for 1st degree and lower
in the 2nd. Depression appears as one of the most frequent phenotype
in affected and their relatives in Manaus, followed by bipolar
disorder.
178
PP213 MAPPING RECESSIVE RISK VARIANTS FOR
SCHIZOPHRENIA IN AN INBRED POPULATION
H. Mansour*(1,2), J. Wood(1), K. Chowdari(1), A. Watson(1), W.
Fathi(2), M. Elassy(2), I. Ali(2), A. Eissa(2), A. Yassin(2), H.
Salah(2), S. Tobar(2), H. Elsayed(2), W. El-Bahaei(2), Z. Gomaa(2),
V. Nimgaonkar(1,3)
1. Department of Psychiatry, University of Pittsburgh School of
Medicine, Western Psychiatric Institute and Clinic, Pittsburgh,
Pennsylvania 2. Department of Psychiatry, Mansoura University
School of Medicine, Mansoura, Egypt 3. Department of Human
Genetics, Graduate School of Public Health, University of Pittsburgh,
Pittsburgh, Pennsylvania
*mansourha@upmc.edu
Introduction: Mapping rare genetic variants in outbred populations
requires very large samples, but may be more facile in inbred
populations by genotyping a handful of patients using homozygosity
mapping (HM). Ancestral chromosomal segments flanking disease
mutations are passed down identical by descent, (IBD). For recessive
diseases, the IBD segments are by definition homozygous by descent
(HBD). We are evaluating the utility of HM for Schizophrenia (SZ),
because our recent studies have shown that SZ is associated with
consanguinity in Egypt (Mansour et al, 2010).
Methodology: Egyptian patients with SZ (n=93, DSM-IV) and adult
controls (n=87) were recruited and genotyped using the Affymetrix
6.0 SNP array. Following quality control procedures, we estimated
homozygous segments using PLINK software, to be confirmed using
Beagle software.
Results: Consistent with published data, consanguineous individuals
are more likely to have longer homozygous segments the mean
homozygous segment length is greater among consanguineous
patients compared with either control groups or non-consanguineous
patients (Figure 1). Several homozygous segments are more frequent
among cases. As we refine our analyses, we will be guided by (i)
genomic regions identified through recent genome-wide association
studies (ii) genomic regions implicated in autism spectrum disorders
(since some risk variants are shared between autism and SZ).
Conclusions: Consanguineous SZ cases are more likely to have
longer homozygous segments. Our analysis showed an HBD
segment on 15q region that shows intriguing case-control
differences. HBD analysis may help detect recessively inherited
chromosomal regions in SZ.

PP214 CANDIDATE GENES FOR AGGRESSION AND
ANTISOCIAL BEHAVIOR: A META-ANALYSIS OF THE 5-
HTTLPR AND MAOA-UVNTR
C. Ficks*, I. Waldman
Emory University
*courtney.ficks@gmail.com
Introduction: Antisocial behavior (behavioral tendencies that reflect
disregard for social norms and the rights of others) is exhibited in
elevated levels in clinical populations and associated with negative
outcomes, such as violent crime, alcoholism, and drug use. Genetic
influences have been estimated to explain approximately 50% of the
variance in antisocial phenotypes. Variation within the serotonergic
system has been associated with aggression in animals and humans,
leading to hypotheses that individual differences within serotonergic
system genes may underlie antisocial phenotypes. Nonetheless,
candidate gene studies examining the main effects of common
variation within serotonergic system genes have yielded small,
inconsistent findings thus far.
Methodology: We conducted a meta-analysis of associations
between antisocial behavior and the two most commonly examined
serotonergic system variants: the serotonin transporter-linked
polymorphic region (5-HTTLPR) of the serotonin transporter gene
and a 30 bp VNTR within the promoter of the monoamine oxidase A
gene (MAOA-uVNTR). Specifically, we examined: 1) whether the
putative "risk” alleles of each marker had significant main effects on
antisocial phenotypes across studies, 2) whether there was significant
heterogeneity in study effect sizes, and 3) whether demographic or
methodological differences contributed to the observed heterogeneity
across studies.
Results: We found small but significant main effects for the 5-
HTTLPR (OR = 1.389, p < 0.001, 95% CI [1.179 - 1.637]), but not
the MAOA-uVNTR (OR = 1.063, p = 0.433, 95% CI [0.913 – 1.237]).
In addition, there was significant heterogeneity in effect sizes for
both markers. Regression analyses suggested that this heterogeneity
could be partially explained by sample age, sex and ethnic
composition.
Conclusions: Overall, it appears that the most commonly examined
serotonergic variants contribute only a small portion of the variance
in antisocial phenotypes, and it is thus important that future studies
focus on additional common and rare variants within these and other
genes known to affect serotonergic function.
179
PP215 GENDER SPECIFIC ASSOCIATION OF
TSNAX/DISC1 LOCUS FOR SCHIZOPHRENIA AND
BIPOLAR AFFECTIVE DISORDER IN SOUTH INDIAN
POPULATION
R. Anjanappa (1), M. Purushottam(1), K. Halagur BhogeGowda (1),
V. Manduva (1), N. Krishna(1), S. Kallahalli Jayramu (1), J.
Yemmiganur Chandrash(1), S. Ghosh(2), S. Jain*(1)
1. Molecular Genetics Laboratory, Department of Psychiatry,
National Institute of Mental Health and Neurosciences 2. Human
Genetics Unit, Indian Statistical Institute (ISI), 203 B.T. Road,
*sjain.nimhans@gmail.com
Introduction: Schizophrenia (SCZ) and bipolar affective disorder
(BPAD) are severe psychiatric disorders, each affecting
approximately 1% of the population worldwide. Family, twin and
adoption studies confirm that genetic factors play a significant role in
the etiology of these disorders. Genetic studies have implicated the
TSNAX/DISC1 in SCZ, BPAD and major depression. This study
was performed to assess the possible involvement of TSNAX/DISC1
locus in the etiology of BPAD and SCZ in the southern Indian
population.
Methodology: We genotyped seven SNPs from TSNAX/DISC1
region in 1252 individuals (419 BPAD patients, 408 SCZ patients
and 425 controls). Association between disease and genotype/allele
frequencies was tested by logistic regression analysis and Chi-square
test.
Results: Logistic regression analysis did not show significance with
the SNPs studied for the gender combined samples. However,
significant allelic association was observed with BPAD as well as the
pooled phenotype of BPAD or SCZ within the female subjects for the
rs766288. Two locus analysis of rs766288 and rs821616 showed C-A
as a risk combination, whereas A-A and A-T appeared as a protective
combination in female cases compared to female
controls. Significant genotypic association was also seen in BPAD
females, SCZ males and in pooled male cases for rs766288. No
positive association was detected for other SNPs studied.
Conclusions: Our results provide further evidence for sex-dependent
effects of the TSNAX/DISC1 locus in the etiology of SCZ and
BPAD in our sample set.

PP216 EXPLORING GENOTYPE-PHENOTYPE
RELATIONSHIPS IN PSYCHIATRIC DISORDERS USING
LATENT SEMANTIC ANALYSIS
R. Breuer*(1), M. Schubert(2), J. Frank(1), M. Mattheisen (3,4,8), F.
Degenhardt(4,9), T. Mühleisen(4,9), T. Consortium(5), S.
Cichon(4,6,9), M. Nöthen(4,9), T. Schulze(7), M. Rietschel(1)
1. Department of Genetic Epidemiology in Psychiatry, Central
Institute of Mental Health (ZI) Mannheim, University of Heidelberg
2. Database Group, Institute for Informatics, Ludwig-Maximilians-
University 3. Department of Biostatistics, Harvard School of Public
Health 4. Department of Genomics, Life & Brain Center, University
of Bonn 5. Department of Psychiatry, University of California 6.
Institute of Neuroscience and Medicine (INM-1), Research Centre
Juelich 7. Department of Psychiatry and Psychotherapy, University
Medical Center, Georg-August-University 8. Institut of Medical
Biometry, Informatics, and Epidemiology, University of Bonn 9.
Institute for Human Genetics, University of Bonn
*rene.breuer@zi-mannheim.de
Introduction: Schizophrenia, bipolar disorder, and major depression
are severe, complex psychiatric disorders with a life-time prevalence
varying between 0.5-1% for schizophrenia and bipolar disorder up to
about 15% for major depression. Heritability estimates range between
50-80% for schizophrenia and bipolar disorder and 30-75% for major
depression. Genome-wide association studies (GWAS) for these three
disorders have so far identified only a few genome-wide significant
associations with small effects. Recently it was shown for human
height that when taking the information content of all tested SNPs
into consideration they can explain roughly half of the reported
heritability. Nevertheless, the question which specific genotype
combinations relate to specific phenotype clusters remains a
challenging and competitive task which requires further approaches.
Methodology: Here, we introduce latent semantic analysis, originally
applied to text mining (Deerwester et al., 1990), as a novel approach
to analyse genome-wide data with respect to various phenotypic
traits. The main principle of this approach is the usage of implicit
higher-order structures in the association of genetic factors with
phenotypic traits. The particular technique used is singular-value
decomposition, which decomposes genotypes and phenotypes into a
set of meaningful orthogonal factors. The decomposition step is
further used to remove noisy implicit structures. In a train-test-set
framework, we explore the ability of this approach to predict the
presence of phenotypic traits in patients with bipolar disorder based
on genotype data.
Results: Latest results from the application to over 3000 patients out
of 3 independent bipolar datasets will be presented: the Genetic
Association Information Network (GAIN) sample, the Translational
Genomics Research Institute (TGEN) sample, and our own German
(BoMa) sample.
Conclusions: An adequate accuracy of this approach should lead to
genotype-phenotype clusters allowing the identification of genetically
more homogeneous subgroups of patients.
180
PP217 GENOME-WIDE SIGNIFICANT INTERACTION BY
CYTOMEGALOVIRUS WITH RESPECT TO RISK OF
SCHIZOPHRENIA
J. Grove*(1,2), D. Demontis(1), M. Hollegaard(3), C. Pedersen(4), T.
Orntoft(5,6), R. Yolken(7), M. Didriksen(8), D. Hougaard(3), C. Wiuf(2), O.
Mors(9), P. Mortensen(4), A. Borglum(1,9)
1. Inst. of Biomedicine, Depts. of Human Genetics, Aarhus University 2.
Bioinformatics Research Centre, Aarhus University 3. Dept. of Clinical
Biochemistry and Immunology, Statens Serum Institut 4. National Centre for
Register-based Research, Aarhus University 5. Dept. of Molecular Medicine,
Aarhus University Hospital 6. AROS Applied Biotechnology A/S 7. The
Johns Hopkins University School of Medicine, Stanley Division of
Developmental Neurovirology 8. Synaptic Transmission, H. Lundbeck A/S 9.
Centre for Psychiatric Research, Aarhus University Hospital
*grove@humgen.au.dk
Introduction: Reports of viral contribution to the aetiology of schizophrenia
(SZ) goes back as far as when psychoses with schizophrenia-like symptoms
were linked to the 1918 influenza pandemic. More recently there have been
many well documented reports of the association of other viruses to SZ.
Infection by cytomegalovirus (CMV) which is of the herpes family, is the
most frequent congenital infection, and has been implicated in a number of
papers for playing a role in the aetiology of schizophrenia (SZ). So far little is
known as to what role CMV may have in the causal pathways leading to SZ.
We carried out a genome-wide environment interaction study with the goal of
detecting interaction with respect to SZ between maternal CMV infection and
the individual SNPs in a GWAS.
Methodology: The study was conducted on a population based, matched
case-control sample. Cases consist of all Danish citizens born from May 1981
who has a SZ (ICD-10 F20) in the Danish Psychiatric Central Registry as of
May 2007. Controls were matched 1-1 to cases by gender and birth date and
selected among those who were not of the same mother as the proband,
resident in Denmark, alive and without a SZ diagnosis at the time the proband
got its first diagnosis and became case. Neonatal dried blood spot samples
were obtained from the Danish Newborn Screening Biobank. DNA was
extracted, whole-genome-amplified and subsequently genotyped on the
Illumina Infinium HD Human610-Quad BeadChip. In the quality control
subjects with call rates below 0.97 were excluded, as were SNPs with call rate

PP218 ON 2X2 AND 2X3 CONTINGENCY TABLES CHI-
SQUARE TESTS FOR RARE VARIANTS
F. Aliev*
Virginia Commonwealth University
*faliev@vcu.edu
Introduction: Genome-wide association studies (GWASs) have
successfully identified thousands of common genetic variants, mainly
common single nucleotide polymorphisms (SNPs), associated with
complex traits, including many common diseases. The power of
association analyses depend on minor allele frequencies (MAF) of
SNPs. For low MAF power of the association test also depends on
contingency table’s approximation with Chi-square distribution. For
small sample sizes this divergence can be handled by using Fisher’s
exact test. For big sample sizes use of Fisher’s exact test is
complicated because of big factorials in the test statistics. In this
study we estimated difference between Chi-square statistics and exact
distribution of the contingency table.
Methodology: We used approximation theory to derive the test
statstics asymptoticv distribution and to find the inflation term from
Chi-square distribution. These estimates allowed us to re-scale Chisquare
distribution and find exact p-values to avoid inflated results.
Then we generated and tested different case-control samples with
MAF’s changing from 0.5% to 5% with same and different case and
control sample sizes.
Results: Theoretical and simulations results show that when minor
allele counts are small in the population there is a shift in asymptotic
Chi-square statistics which results in inflated p-values. The length of
the shift depends on minor allele counts and as a result p-values of
the associations look smaller than exact p-values.
Conclusions: Our study shows that correction for small MAF has to
be made to Chi-squared statistics to get more precisious p-values.
181
PP219 NEUREGULIN AND DOPAMINERGIC GENES: RISK
FACTORS FOR SCHIZOPHRENIA IN MALAYSIAN
POPULATION
S. Tee*, P. Tang, H. Loh
Universiti Tunku Abdul Rahman
*teesf@utar.edu.my
Introduction: Schizophrenia is a complex psychotic disorder with a
lifetime prevalence of approximately 1%. Susceptibility of some
genes at many genetic locations with small penetrance is suggestive
of thismultigenicdisorder. Molecular components of the neuregulin
genes and dopaminergic systems may play an important role in the
pathophysiology of SCZ. Dopamine D3 receptors (DRD3)
concentrated in limbic regions of the brain may be particularly
relevant to SCZ. The enzyme catechol-O-methyltransferase (COMT)
is crucial for the inactivation of prefrontal dopamine. Besides, the
role of the neuregulin system has been implicated in the etiology of
SCZ. Substantial studies have placed the neuregulin genes (NRG1),
DRD3, COMT and in the limelight as candidategenes for human
psychotic disorders.
Methodology: In this study, we assessed the associations between
SCZ and single nucleotide polymorphisms (SNPs) of NRG1, Ser9Gly
DRD3, COMT rs4680 and with Malaysia cases-control. A total of
267 schizophrenic patients and 250 healthy controls were recruited.
Polymerase chain reaction-restriction fragment length polymorphism
(PCR-RFLP) was performed to genotype these three SNPs and
analyzed with HWE and Chi-square test.
Results: Our results suggest that the polymorphisms at theNRG1,
DRD3 and COMT rs4680 genes are susceptible to SCZ. Individual
SNP analysisshowed that bothgenotype and allele frequencies ofthese
three SNPs were significantly (p < 0.05) associated with SCZ in the
Malaysian population.
Conclusions: Further studies are needed to validate the role of these
polymorphismsalthough positive associations among NRG1, Ser9Gly
DRD3 and COMT rs4680 and polymorphisms were found in the
Malaysian population.

FUNCTIONAL GENOMICS & MODEL
ORGANISMS
PP220 NO ASSOCIATION OF COMT VAL158MET
POLYMORPHISM WITH SUICIDAL BEHAVIOR: META-
ANALYSIS AND NEW DATA
S. Pool García*(1), I. Juárez Rojp(2), T. Frias-Ramón(2), D.
Bermudez Ocaña(2), A. Jimenez Santos(2), M. Villar Soto(3), M.
Sanchez(1), B. Camarena Medellin(4), A. Genis(5), N. Humberto(5),
C. Tovilla-Zarate(2)
1. Hospital General de Comalcalco, Tabasco. Secretaria de Salud 2.
Universidad Juárez Autónoma de Tabasco, División
Multidisciplinaria de Comalcalco 3. Hospital de alta especialidad
“Gustavo A. Rovirosa P" 4. Departamento de Genética Psiquiátrica,
Instituto Nacional de Psiquiatría “Ramón de la Fuente Muñiz” 5.
Grupo de estudios medicos y familiar Carracci
*shepoga70@hotmail.com
Introduction: The polymorphism COMTval158met has been
associated with suicidal behavior in cases-control and meta-analysis
study but results and conclusions remain controversial. The objective
of this study we examined the association between COMT val158met
and suicide behavior in a cases-control and for assess the combined
evidence we realized a meta-analysis study
Methodology: We conducted a cases-control study with 105 patients
with suicide attempter and 236 controls. Subsequently we performed
a meta-analysis of published genetic association by searching through
Medline, PubMed and Wev of Science databases
Results: No significant differences were found in the distribution of
alleles (χ2=0.33, 1 df, p=0.56), or genotypes (χ2=2.36, 2 df, p=0.26).
The meta-analysis comprising 12 association studies (including the
present one) showed that the risk allele COMTmet of
COMTval158/met is not associated with suicidal behavior (OR: 1.09,
95% CI: 0.97-1.23) in the absence of heterogeneity (OR: 1.09, 95%
CI: 0.97-1.23)
Conclusions: Our results showed no association between
COMTval158/met and suicidal behavior. However, more studies are
necessary to determine an association between COMT and suicidal
behavior
182
PP221 GENOME-WIDE EXPRESSION PROFILING OF
WHOLE BLOOD FROM HEAVY CANNABIS USERS AND
CONTROLS REVEALS DIFFERENTIAL REGULATION OF
TWO RELEVANT GENES
C. Schubart*(1), S. de Jong(3), E. Janson(3), W. van Gastel(1), I.
Sommer(1), R. Kahn(1), R. Ophoff(2,3), M. Boks(1)
1. Rudolf Magnus Institute of Neuroscience, University Medical
Centre Utrecht 2. UCLA Center for Neurobehavioral Genetics 3.
Dept of Medical Genetics, University Medical Centre Utrecht
*c.schubart@umcutrecht.nl
Introduction: With over 165 million users worldwide, cannabis is
the most frequently used illicit drug and is associated with a variety
of adverse effects of which many are (neuro-) psychiatric.
Particularly the association with psychotic disorders is clinically
meaningful and reproduced repeatedly. However, little is known
about the biological mechanisms by that underlie these associations.
Gene-expression profiling is a valuable hypothesis generating tool to
unravel the biological mechanisms underlying the adverse effects
associated with cannabis use. We here report a genome wide
expression profiling study in whole blood from heavy cannabis users
and controls that reveals differential regulation of two relevant genes.
Methodology: We selected 190 subjects, 90 heavy users and 100
cannabis naïve subjects. All subjects were assessed using
standardized structure clinical interviews (SCID, CIDI). Genomewide
RNA expression profiling was obtained with HumanRef-12
arrays using Illumina’s standard protocol. Gene expression data were
transformed, normalized and filtered. Gene-expression was tested for
association with cannabis status (with age, gender, smoking and other
drug use as covariates) using linear model regression analysis
implemented in the limma R package. FDR correction for multiple
testing was applied.
Results: The expression of two transcripts CX3CR1 (LogFold
Change -0.42456) and PPFIA2 (LogFold Change 0.168589) was
significantly associated with cannabis use.
Conclusions: The chemokine receptor CX3CR1 is expressed on
neurons and may play a role in neuronal survival. Two previous
studies involved the CX3C receptor-ligand system in gene expression
changes induced by cannabinoids in mouse brain and isolated
astrocytes. PPFIA2 encodes a protein that is a member of the LAR
protein-tyrosine phosphatase-interacting protein (liprin) family. In
interaction with liprins, these proteins are known to moderate axon
guidance. Moreover liprin proteins are thought to be involved in
synapse maturation. We are not aware of previous studies that
investigate genome wide gene-expression gene expression changes in
whole blood associated with cannabis use in humans. The two
transcripts that were found to be genome wide differentially
expressed in heavy cannabis users compared to cannabis naïve
individuals are plausible candidates to help us further understand the
etiology of (psychiatric-) adverse effects associated with cannabis
use.

PP222 ENHANCED EXPRESSION OF TRANSCRIPTION
FACTOR SP1 IN POSTMORTEM BRAIN TISSUES AND
ALTERED REGULATION OF SEVERAL AUTISM
CANDIDATE GENES
T. Ismail*(1), A. Ayyappan(2), K. Nakamura(1), S. Suda(3), H.
Matsuzaki(2), N. Mori(1,2)
1. Department of Psychiatry and Neurology, Hamamatsu University
School of Medicine 2. Research Centre for Child Mental
Development, Hamamatsu University School of Medicine 3.
Department of Psychiatry, Jichi Medical University
*thanseem@hama-med.ac.jp
Introduction: The prevailing hypothesis suggests autism as a
polygenic disease, in which, multiple genes, each with a small effect,
are involved in predisposition to the development of the disorder.
Thegeneral view,points totheinvolvement of epigenetic mechanisms
in autism, where susceptibility genes interplay with environmental
factors as well as with other modulating genes and, due to such
complexity, variable clinical features are incurred. Specificity protein
1 (Sp1) is a zinc finger (Cys2/Hys2) DNA-binding transcription factor
that binds to and acts through the GC-box promoter elements of
genes. This ubiquitous transcription factor is known to regulate the
expression of a variety of genes. Interestingly, Sp1 binding sites have
been reported in the promoter regions of several genes, which are
implicated in autism. Since profound changes in gene expression can
result from abnormalities in the concentrations of sequence-specific
transcription factors, we hypothesize that Sp1 might be a regulator of
the susceptibility genes of autism abnormalities of Sp1 may account
for the heterogeneity observed in this disorder.To examine this
hypothesis, we investigated whether the Sp1 gene is abnormally
expressed in autism brains, and consequently, can affect the
expressions of potential candidate genes implicated in this disorder.
Methodology: The brain samples were obtained from the Autism
Tissue Program and the Harvard Brain Tissue Resource Centre. The
mRNA expressions of Sp1 and that of reported autism candidate
genes (with promoterbindingsites for Sp1) were analyzed in the
postmortem brain tissuesof autism patients (n=8)and healthy controls
(n=13)with q-RTPCR using TaqMan gene expression probes.
Furthermore, alterations in the autism gene expressions were studied
in the SK-NH neuronal cell lines upon (i) Sp1/DNA binding
inhibition using mithramycinA, and (ii) Sp1 gene silencing by RNAi.
Results: We observed elevated expression of Sp1 in the anterior
cingulate gyrus (ACG) of autism patients (p=0.010). We also
observed altered expressions of several autism genes. GABRB3 and
HTR2A showed reduced expressions, while CD38, ITGB3, MAOA,
MECP2, OXTR and PTEN showed elevated expressions in autism. In
SK-N-SH cells, OXTR, PTEN and RELN showed reduced expressions
upon Sp1/DNA binding inhibition and Sp1 silencing.
Conclusions: The results indicate that transcription factor Sp1 may
bedysfunctional in autism. Anelevated expression of Sp1 in autism
indicates the possible involvement of this transcription factor in the
gene expression alterations underlying the pathology of this
disorder.Consequently, the expressions of potential autism candidate
genes, OXTR, PTEN and RELN, regulated by Sp1, could be affected.
The diverse downstream pathways mediated by the Sp1-regulated
genes, along with the environmental- and intracellular signal- related
regulation of Sp1, could explain the complex phenotypes associated
with autism.
183
PP223 NEUROPHYSIOLOGICAL FEATURES OF
PERCEPTION OF EMOTIONAL STIMULI AND THEIR
RELATIONSHIP TO THE GENETIC FACTOR IN
SCHIZOPHRENIA
A. Arkhipov*
Institute of Higher Nervous Activity and Neurophysiology RAS
*arhip76@bk.ru
Introduction: It is assumed that in schizophrenia there is an
infringement of the spontaneous and evoked brain activity during
perception of emotional stimuli. In the psychotic period, there is a
significant violation of the neural networks associated with
perception and processing of emotional stimuli, but their remission is
some recovery. Genetic factors influence the severity of pathological
rearrangements of neural networks in schizophrenia as a psychotic
period and during remission.
Methodology: Methods were used:The PANSS. Registration and
processing of EEG during perception of pleasant, neutral, and
threatening visual stimuli.Fence venous blood for DNA extraction by
phenol-chloroform method (Maniatis 1984). Polymerase chain
reaction (PCR) to determine allelic polymorphism: DAT-1 gene
dopamine transporter, EAAT-2 glutamate transporter gene, GAT-3
GABA transporter gene, Val66Met gene BDNF. Statistical methods:
ANOVA, Wilcoxon's test, Mann-Whitney test, correlation analysis.
Results: The combination of some of the changes of allelic
polymorphism of DAT-1 gene dopamine transporter, EAAT-2
glutamate transporter gene, GAT-3 GABA transporter gene,
Val66Met BDNF gene determinesneurophysiological disorders in
schizophrenia.
Conclusions: Nature of the rhythm of the brain in different ranges of
cortical and subcortical structures in subjects with schizophrenia in
acute psychotic period, different from the remission period and differ
from healthy, which is caused by genetic factors. The stronger the
neurophysiological changes in the psychotic period, the less stable
remission, the severity is caused by genetic factors.

PP224 MOLECULAR AND CELLULAR
CHARACTERISATION OF A BRAIN-SPECIFIC
TRANSCRIPTIONAL REGULATOR
A. Kepa*, S. Desrivières
MRC-SGDP Centre, Institute of Psychiatry, Kings College London
*agnieszka.kepa@kcl.ac.uk
Introduction: Abnormalities in brain development and maladaptive
plasticity underlie a range of neurodevelopmental and neurological
disorders. Therefore, there is a need to identify genes and pathways
involved in these processes. Transcription factors (TFs) play a pivotal
role in brain development by directing the formation of neurons and
glia from uncommitted progenitor cells and by controlling expression
of neural-specific genes. The myelin transcription factor 1- like
(MYT1L) gene product, a transcription factor specifically expressed
in the brain, has recently been shown to be one of three factors
sufficient to transform fibroblasts into neurons, suggesting a central
role for this protein neural cell function. Our recent quantitative trait
loci (eQTL) analyses have revealed networks of putative downstream
target genes through which MYT1L might regulate neurite
development and morphogenesis. We aim at validating these findings
using appropriate cellular models. We also aim at better
understanding the biological function of this gene by identifying
putative upstream regulators.
Methodology: We will express MYT1L as native or recombinant
protein (with a C-terminal V5 epitope) into human neural (SH-SY5Y,
neural progenitor) and non-neural (HEK293T) cell lines. Effects of
enhanced MYT1L expression on mRNA levels of putative
downstream targets will be measured by real-time RT-PCR. Cells
expressing recombinant MYT1L will be used to identify MYT1Lcontaining
protein complexes following immunoprecipitation with
anti-V5 antibody, elution co-immunoprecipitating proteins and their
separation of by SDS-PAGE. Identification of isolated protein bands
will be performed by liquid chromatography-mass spectrometry.
Results: We have constructed lentiviral expression vectors in which
MYT1L is expressed either as a native protein or fused to a Cterminal
V5 epitope. These viruses are currently used to transduce
various lines of human cells. RNA extracts from these cells will be
used for the identification downstream targets of MYT1L. Protein
extracts of MYT1L-V5 expressing cells will be used for
immunoprecipations. Results of these experiments will be presented.
Conclusions: Identification of genes and pathways acting upstream
and downstream of MYT1L will help us to understand the
mechanisms by which this gene regulates neural differentiation. Such
findings are expected to provide a greater understanding of normal
brain development and have important implications by identifying
genes and genes pathways that might be deregulated in
neurodevelopmental and neurological disorders.
184
PP225 A NOVEL, DIET-INDUCED, MURINE MODEL OF
OBSESSIVE-COMPULSIVE DISORDER
D. Trujillano*, J. McDonald, M. Gratacós, M. Dierssen, X. Estivill
Genes and Disease Program, Center for Genomic Regulation (CRG-
UPF)
*daniel.trujillano@crg.eu
Introduction: The main purpose for the development of animal
models for Obsessive-Compulsive Disorder (OCD) is to use them for
the study of the neural mechanisms underlying this disorder and
developing novel treatments. The majority of these OCD animal
models involve acute, drug-induced symptom provocation or genetic
alterations associated with stereotypies or anxiety. Here we present a
novel, diet-induced OCD murine model that demonstrates multiple
OCD-like behaviors.
Methodology: Young mice were given free choice between standard
chow and a palatable, chocolate diet using the PHECOMP (Panlab)
food and drink monitoring system. Cases and controls were tested for
multiple OCD-like behaviors, including marble burying and nestlet
shredding.
Results: Two weeks after the start of the experiment, treated mice
developed a compulsive feeding pattern accompanied by the
apparition of multiple OCD-like behaviors. This behavioral data is
supported by molecular data suggesting a deregulation in the
expression of various serotonin and dopamine receptors in different
areas of the brain, including the striatum, the frontal cortex and the
thalamus.
Conclusions: This is a novel, multiple-symptom, diet-induced OCD
murine model that shows behavioral changes accompanied by
biochemical changes in brain regions directly involved in the
pathophysiology of OCD. Moreover, this OCD model also warns us
about the physical and mental consequences of the abuse of a
cafeteria diet.

PP226 FUNCTIONAL STUDY OF THE
ENDOCANNABINOID SYSTEM USING POSTMORTEM
BRAINS AND RODENT MODELS OF FEAR AND STRESS
K. Choi*(1), G. Xing(1), T. Le(1), J. McGuire(1), L. Zhang(1), H.
Li(1), L. Johnson(1), M. Webster(2), D. Benedek(1), R. Ursano(1)
1. Dept. Psychiatry, Uniformed Services University of the Health
Sciences 2. Stanley Medical Research Inst.
*kwang.choi@usuhs.mil
Introduction: Posttraumatic stress disorder (PTSD) is an anxiety
disorder that affects approximately 7% of the population in the US.
Core symptoms of PTSD include re-experiencing,
avoidance/numbing and hyper-arousal. Individuals with PTSD
experience significant functional impairment such as occupational
and social dysfunction, as well as physical and mental health
problems. There is evidence to suggest the endocannabinoid system
is involved in mood and anxiety disorders and may be an important
drug target for the treatment of PTSD. Animal and human studies
indicate that endocannabinoid receptors (CNR1 and CNR2) may
regulate fear conditioning/extinction and peri-traumatic dissociation
symptoms.
Methodology: We investigated expression profiles of CNR1 and
CNR2 in the prefrontal cortex (PFC) of humans and rodents using
data from gene expression microarrays and quantitative PCR. The
subjects include a developmental cohort of normal individuals
ranging in age from birth to 50 years of age, a cohort of mood
disorder patients and unaffected age-matched controls, rats exposed
to restraint and tail-shock stress and mice selectively bred for high
and low fear phenotypes.
Results: We found that the expression profiles of endocannabinoid
receptors are age-dependent and disease-specific. For example,
CNR1, but not CNR2, levels gradually decrease in the PFC during
postnatal brain development. CNR1 mRNA levels decrease following
exposure to restraint and tail-shock stress, whereas CNR2 levels
appear to increase, in the PFC of female rats. In mood disorder
patients, CNR2 levels were differentially expressed between bipolar
disorder and major depression. A study is in progress to measure
mRNA levels of CNR1 and CNR2 in the PFC of high and low fear
mice following fear conditioning and extinction of fear memory.
Conclusions: Our results suggest that expression levels of
endocannabinoid receptors in the brain are altered following exposure
to stress and anxiety. Our translational approach combines data from
animal models of stress and from postmortem brains with mood
disorders to enhance our understanding on the molecular mechanisms
that may underlie these disorders. More research is needed to
determine the functional significance of the endocannabinoid system
in individuals with stress and anxiety disorders.
185
PP227 KNOCKDOWN OF PBRM1, A PUTATIVE RISK GENE
FOR MOOD DISORDER AND SCHIZOPHRENIA, INDUCES
WIDESPREAD ALTERATIONS IN GENE EXPRESSION,
CELLULAR MORPHOLOGY, AND PROLIFERATION
X. Jiang*, S. Detera-Wadleigh, F. McMahon
NIMH
*sjiang1@mail.nih.gov
Introduction: A meta-analysis of genome-wide association studies
(GWAS) in mood disorders found the strongest evidence of
association at a synonymous SNP in PBRM1 (McMahon et al
2010). The same SNP has been shown to be associated with
schizophrenia (Williams et al. 2011). Although several genes map to
the same ~350 kb linkage disequilibrium region on chromosome
3p21.1, in GWAS "the causal gene will often be located near the
most strongly associated DNA variant"(Allen et al. 2010), so we
have undertaken initial functional studies of PBRM1.
Methodology: We employed a loss-of-function paradigm by
generating a stable knockdown of PBRM1in both HeLa and SHSY5Y
neuroblastoma cells via lentiviral-mediated transduction of short
hairpin (sh) RNA. Differential gene expression profiles examined
using the Illumina Human HT 12v3 Expression Bead Array.
Results: PBRM1 knockdown generated 129 overexpressed and 70
underexpressed genes.Notably, PBRM1 knockdown induced a
significant downregulation of PDE4B, which encodes cAMP-specific
3’5’ phosphodiesterase 4B. This protein is known to interact with
DISC1 (Millar et al. 2005), and altered phosphodiesterase signaling
has been reported in both mood disorders and schizophrenia. We
further found that the underexpression of PDE4B after PBRM1
knockdown was partially reversed by valproate, consistent with its
therapeutic role in bipolar disorder. PBRM1 encodes polybromo1
(aka BAF180), which isthe chromatin binding component of the
Brahma-associated factor (BAF) nucleosome remodeling complex
(Ho & Crabtree 2010). It is therefore interesting that of the 27
histone-related genes that were represented on the array, 9 were
differentially expressed after PBRM1 knockdown, and all of these
were upregulated at least 1.8-fold. HeLa and SHSY5Y cells with
stable PBRM1 knockdown displayed strikingly slower proliferation
and altered cellular morphology,suggesting a possible role for this
gene in cell cycle control and apoptosis.
Conclusions: If PBRM1 plays a causal role in mood disorders and
schizophrenia, this role may be mediated by widespread changes in
the expression of genes involved in signal transduction, chromatin
remodeling, and cellular development. This study demonstrates the
value of GWAS findings in directing studies to diverse biological
processes potentially involved in disease etiology.

PP228 GLOBAL TRANSCRIPTOMIC AND PROTEOMIC
CHARACTERIZATION OF ANTIDEPRESSANT DRUGS AND
STRESS RESPONSE IN A MOUSE MODEL OF DEPRESSION
K. Malki, R. Uher, J. Payo-Cano, E. Binder, K. Aitchinson, I. Craig,
J. Campbell*, P. McGuffin, L. Schalkwyk
Institute of Psychiatry
*james.campbell@kcl.ac.uk
Introduction: Selective serotonin reuptake inhibitors (SSRIs) and
Noradrenergic reuptake inhibitors(NRI’s) represent two class of
antidepressant drugs with varying pharmacodynamic and
pharmacokinetic mode of action that have been shown to be clinically
effective in the treatment of depression. However biomarkers with
the power to predict responders to each drug class are not yet
established and prescription still follows a trial and error protocol.
The GENDEP study was designed to uncover genetic markers of
antidepressant response by integrating findings from a large scale
human pharmacogentic, in-vitro and animal study using the same two
antidepressants across all of its treatment arms. In this paper we
report findings from from the mouse arm of the GENDEP project.
Methodology: Expression profiles derived from the hippocampus
tissue of 4 inbred mouse strains (DBA, FVB, C57 and 129) of both
sexes, treated with varying dose (chronic and acute) of either
nortriptyline (NRI) or escitalopram(SSRI) and subjected to two
different types of depressogenic protocols (maternal Deprivation and
Chronic Mild Stress) were analysed using the Affymetrix MOE 430
V2 expression chip. Quantitative proteomic analyses were undertaken
on hippocampal tissue from a subset (18) of the 144 experimental
groups used for the transcriptomic analysis. Complementary
approaches, namely two dimensional polyacrylamide gel
electrophoresis (2DE) and isobaric tandem mass tagging (TMT),
were applied to the selected experimental cells.Multivariate and
machine learning methods were used to uncover candidate genes and
genes products differentially expressed in response to the two drugs
tested.
Results: The results highlighted significant strain and stress related
differences across both transcriptomic and proteomic data sets. The
most compelling results is the identification of three gene products
involved in serotonergic (PXBD5, YHWAH, SLC25A4) and one in
noradrenergic antidepressant action (PXBD6). Specifically YWHAB
was significantly up regulated in response to SSRI treatment. It
belongs to a large family of 14-3-3 proteins that participate in a
number of important cellular processes implicated in depression and
antidepressant treatment including cell signalling, apoptosis and the
stress response. It is both a brain specific and highly conserved
(>99%) between currently studied eukaryotes including drosophila,
yeast, human rat and mouse. SLC25A4 is part of the mitochondrial
carrier subfamily. Recent studies have suggested that mitochondrial
dysfunction may play a role in the pathogenesis of unipolar
depression and the SLC25A4 gene and has previously been
implicated in this process.
Conclusions: The search for candidate genes is limited by both our
incomplete understanding of the aetiology of depression and the
mechanism of action of therapeutics drugs. Animal models allow for
a hypothesis free search for genetic variants associated with treatment
response and allow for gene expression to be measured in depressionrelevant
brain regions. However mRNA analysis alone cannot
capture information on post transcriptional and regulatory factors or
predict the effect of transcriptional control on protein translation, the
effect of gene-gene interaction and other post-transcriptional
factors. Proteomic approaches are therefore useful to complement
the analysis at the transcriptome level to obtain a more
comprehensive characterisation across the functional
genomics. Candidate genes emerging from this study will be
used to inform prioritisation in human pharmacogentic studies.
186
OTHER
PP229 NO ASSOCIATION BETWEEN THE HTR1A GENE
AND SUICIDAL BEHAVIOR: A META-ANALYSIS
M. Rivera Angles*(1), D. Bermudez Ocaña(1), I. Juárez Rojop(1),
B. Camarena Medellin(2), A. Genis(3), T. Frias Ramón(1), H.
Nicolini(3), C. Tovilla-Zarate(1)
1. Universidad Juaréz Autónoma de Tabasco, División Académica
Multidisciplinaria de Comalcalco 2. Departamento de Genética
Psiquiátrica, Instituto Nacional de Psiquiatría “Ramón de la Fuente
Muñiz”, 3. Grupo de Estudios Medicos y familiares Carracci
*miriam_angles@hotmail.com
Introduction: Dysfunction of serotonin 1A receptors (HTR1A) may
play a role in the genesis of suicidal behavior. We studied the
association between a functional polymorphism in the gene HTR1A
and suicidal behavior
Methodology: We performed a meta-analysis of published genetic
association studies by searching through Medline, PubMed and Web
of Science databases to analyze a possible correlation between the
rs6295 polymorphism and suicidal behavior in different populations
Results: Four were the eligible studies comprising a total of nine
hundred and fifty seven patients with suicidal behavior and nine
hundred and fifty seven controls. The allele G of the rs6295
polymorphism could not be associated with suicidal behavior
(Random-effects model: OR:1.08 95%CI:0.80-1.45 p(Z)=0.80) in
presence of heterogeneity (Q=17.84, df =4, p=0.0013). In a second
analysis that presented no heterogeneity, a negative association was
also observed (OR: 0.94 95%CI: 0.79-1.13 p(Z)=0.99).
Conclusions: To our knowledge, the present study is the first metaanalysis
looking for a correlation between rs6295 of HTR1A and
suicidal behavior. Our results showed no association between
HTR1A and suicidal behavior. However, more studies are necessary
that include other populations, as well as larger samples

PP230 GLUTAMATERGIC PATHWAY DISSECTION AND
INDICATIONS FOR GENETIC ASSOCIATION STUDIES IN
MAJOR DEPRESSIVE DISORDER
C. Crisafulli*(1), A. Drago(2), A. Sidoti(1), D. De Ronchi(2), A.
Serretti(2)
1. Department of Biomorphology and Biotechologies, Division of
Biology and Genetics, University of Messina 2. Institute of
Psychiatry, University of Bologna
*ccrisafulli@unime.it
Introduction: The glutamatergic pathway has been consistently
involved in the physiopathology of depressive disorder, however a
complete dissection and integration of its role in the context of other
known mechanisms is lacking. We summarized and integrated the
evidence of various levels of interaction between glutamatergic and
monoaminergic pathways to provide a detailed list of possible
candidates with practical suggestions for association studies planning.
Methodology: We identified six molecular pathways, some of which
with specific regional distribution within the brain. From the six
pathways we identified the key proteins and their coding genes.
Hapmap database (hapmap.ncbi.nlm.nih.gov) served for the
identification of the tagging variations. Pubmed database
(http://www.ncbi.nlm.nih.gov) served for the identification of all the
validated variations and functional variations for each candidate. All
the identified validated variations for each candidate were forced as
input in the Hapmap dataset in order to retrieve the maximum
coverage of each candidate under a tagging approach.
Results: Reviewing the lines of evidence of two fundamental
theories of major depressive disorder (MDD) we disentangled six
main metabolic pathways that could be pivotal in the
pathophysiology of the disease: the CAM kinase II, the MAP kinase
and ERK, PKA and PKC, the inositols pathway, the NO cascade, the
axon guidance and actin cytoskeleton and the cellular death pathway.
Conclusions: We obtained a list of pivotal enzymes out of which we
numbered the covering genetic variations. Such coverage may
provide a genetic framework to serve future genetic association
studies.
187
PP231 INVESTIGATING GENE EXPRESSION CHANGES IN
THE HIPPOCAMPUS AND HYPOTHALAMUS FOLLOWING
A MATERNAL SEPARATION PARADIGM IN TWO INBRED
STRAINS OF MICE
T. Powell*, R. Kember, J. Mill, C. Fernandes, L. Schalkwyk
King's College London
*timothy.powell@kcl.ac.uk
Introduction: Gene-environment interaction (GxE) studies have
shown that the existence of susceptibility genes (G) in the presence of
early life stress (E) increases the chances of developing later life
depression. The current study aimed to further investigate the effects
of early-life stress using a maternal separation paradigm.
Methodology: Two inbred strains of mice, C57BL/6J and DBA/2J,
were used to establish whether different genetic strains (G) in the
presence of the same early life stress (E) showed differential gene
expression (GxE) in two key brain regions related to the
pathophysiology of depression. Mice were assigned to either a
control (n=22) or separated group (n=18). Separated groups
underwent maternal separation at postnatal day 9 for 24hours, control
and separated groups then underwent behavioural testing at week 12
(discussed briefly) and culling at week 15. The hippocampus and
hypothalamus were dissected and RNA was extracted and used for in
vitro cDNA synthesis. cDNA was then fragmented and hybridised for
use on Affymetrix Gene Chip microarrays.
Results: Results discussed include any notable gene-environment
interactions as well as strain-specific and tissue-specific expression
differences.
Conclusions: Using mouse models to manipulate environments at
different developmental stages in relation to genetic backgrounds is
useful in gaining a unique insight in the complicated pathological
processes involved in disorders such as depression.

PP232 SEQUENTIAL SCREENING OF MUTATIONS
MEDIATED BY ALU IN SCHIZOPHRENIA
M. Ueno*, A. Akahane, T. Hata, S. Nanko
Teikyo University School of Medicine
*mueno@med.teikyo-u.ac.jp
Introduction: In previous reports, we have identified the de novo
mutations mediated by mobile elements in the patients with
schizophrenia. These dynamics of mobile elements is not fully fixed,
and might be progressively after event onset. Herein, we have
attempted the sequential screening of mutations mediated by mobile
element Alu in patients.
Methodology: DNA samples were obtained from a patient and a
control subject. Sequential collection of blood was performed at
intervals of 5 years. At first screening, the microarray assay using
Alu-PCR products from each sample was performed to detect the
mutated genes. Second, Fluorescent in situ hybridization(FISH)
analysis was performed on combed DNA using AluYa5 probe and
BAC probes which were containing the genes screened by
microarray. This study was done under the approval of the Ethical
Committee for Genetic Research, Teikyo University School of
Medicine.
Results: We have identified the progressive mutations mediated by
Alu. The microarray assay allows us to clear the characteristic of
patient genome. The 24 of 26 progressive mutations in the patient
were deletion types. Moreover, FISH analysis on TPM4 gene with
progressive deletions showed the decreasing signals of Alu probe in
patient.
Conclusions: Our results suggested that the dynamics of Alu might
be one of the risk factors for schizophrenia. Recently, the dynamics
of mobile element L1 have been reported to contribute to the
neuroplasticity in adult brain. Further research using sequential
screenings of various mutations mediated by mobile elements is
needed to clarify the etiology in schizophrenia.
188
PP233 CENTRAL CNS NEONATAL LESION IN VENTRAL
HIPPOCAMPUS MAY ALTER PERIPHERAL
LYMPHOCYTE DOPAMINE GENE EXPRESSION
A. Genis*(1,4), C. Lopéz-Rubalcava (2), J. Flores(4), P. Mendoza(3),
P. Ostrosky(3), H. Nicolini(1,4)
1. Universidad Autónoma de la Ciudad de México 2. Centro de
Investigación y de Estudios Avanzados del IPN 3. Instituto de
Ciencias Biomédicas 4. Servicios de atención psiquiátrica
*genis76@yahoo.com
Introduction: The animal model of neonatal lesion in the ventral
hippocampus (NLVH) is a wide validated animal model used to study
schizophrenia from a neurodevelopmental focus. This animal model
is also used to investigate how neonatal lesion may alter genetic
expression of dopaminergic receptors. Some researchers have
observed changes in the expression of drd2/drd3 in patients with
schizophrenia in lymphocytes of peripheral blood. These studies have
shown that schizophrenic patients have increased expression of
mRNA-drd2. Literature indicates that NLVH causes improper
maturation of inter-neurons from the prefrontal cortex, that may
produce a hyperactive or irregularly active cortex. This condition has
been proposed as a mechanism underlying dysfunction in the PFC
and other cortical areas that may explain some schizophrenic
characteristics. Studying CNS tissue in schizophrenic patients is not
easy, however, peripheral markers that can be easily obtained and
that could be related to the disease process are necessary.
Methodology: NLVH procedure was applied to male Wistar rats at
5-7 days after birth. At postnatal days 45 and 90, locomotor activity,
social interaction, object recognitionand prepulse inhibition were
analyzed. In addition drd2 and drd3 expression in lymphocytes were
measure. All behaviors and receptor expressions were compared with
those of sham the operated group.
Results: Quantification of drd2 showed significant over-expression
with respect to the control sample in contrast drd3 expression didn't
change neither at 45 or 90 days of age. In 90 days old rats, an
increase in locomotor activity and a reduction in memory, prepulse
inhibition and social interaction behaviors in comparison to the sham
group were observed. The drd2 expression was observed only in the
experimental group with 90 days-age. It is important to indicate that
although the five dopaminergic receptors are present in lymphocytes
of peripheral blood, the expression of drd2 is not observed in healthy
animals without manipulation or sham operated group nevertheless
when these animals reach adulthood, drd2 is expresses mainly due to
the response of the lesion performed at neonatal time.
Conclusions: This change in drd2 expression could serve in the
future as a molecular marker for schizophrenia, since expression in
peripheral blood of rats with NLVH correlate with rat's
schizophrenic-like behaviors that reflect some symptoms of the
disease.

PP234 GENE EXPRESSION PROFILE OF PERIPHERAL
BLOOD DISCRIMINATES PATIENTS WITH
SCHIZOPHRENIA SUBMITTED TO DISTINCT
TREATMENTS
A. Silva*(1), H. Brentani(2), C. Pereira(3), D. Carraro(1), R.
Puga(1), B. Mello(1), M. Maschieto(1), P. Belmonte-de-Abreu(4), J.
Palha(5)
1. Research Center, A C Camargo Hospital 2. Institute of Psychiatry,
University of Sao Paulo, Medical School 3. Institute of Mathematics
and Statistics, University of Sao Paulo 4. Department of Psychiatry,
Federal University of Rio Grande do Sul 5. Life and Health Sciences
Research Institute, School of Health Science, University of Minho
*aderbs@gmail.com
Introduction: Schizophrenia is a debilitating psychiatric disorder
considered as a “two-hit” disease, with a neurodevelopmental
impairment followed by an additional hit in early adulthood. Both
events are regulated by hormonal (like thyroid and retinols) and
signal transduction pathways (like Wnt signaling pathway), which
have already been identified in post-mortem brain studies of
schizophrenic individuals. While brain studies are fitted for
pathology assessment post-mortem, there is not suitable material for
searches of a schizophrenia “diagnostic signature” in live patients.
There is still a requirement to identify a feasible material to be used
in the investigation of molecular markers useful for diagnosis in
schizophrenia patients.
Methodology: Gene expression profile of blood from twenty eight
males with DSM-IV schizophrenia under three drug regimens
(clozapine, risperidone or haloperidol), and ten healthy controls were
analyzed in a cDNA microarray platform containing 1,364 genes
implicated with hormonal and signal transduction pathways.
Significant Analysis of microarray using TMEV software identified
differentially expressed genes.
Results: Seven genes were differentially expressed between controls
and patients with different treatments, and 28 between healthy
controls and specific treatments. CTNNA1, GSTM3, HOXA-13 and
KRT18 were commonly altered in all analyses. Furthermore, principal
component analysis based on the differentially expressed genes
expression values discriminated clozapine- (CLO), risperidone-
(RIS), haloperidol-treated (HAL) patients and the healthy controls
(Cont) (Figure 1).
Conclusions: These results suggest that it is feasible to use peripheral
blood, an accessible material, from patients for studying
schizophrenia. Also, this study revealed genes which expression
might be modulated by drug treatments.
189
PP235 APOLIPOPROTEIN H (APO H) AS NOVEL
BIOMARKER FOR SCHIZOPHRENIA
H. Loh*(1), T. Chow(2)
1. Centre for Healthcare Science and Technology, Faculty of
Engineering and Science, Universiti Tunku Abdul Rahman 2.
Department of Science, Faculty of Engineering & Science, Universiti
Tunku Abdul Rahman
*hcloh@utar.edu.my
Introduction: Biomarkers for Schizophrenia (SCZ) are essential to
facilitate disease diagnosis ideally at early stages, monitor disease
progression and assess response to existing and future treatments.
Application of proteomics to the human brain, cerebrospinal fluid and
serum has greatly hastened the unbiased and high-throughput
searches for novel biomarkers.
Methodology: Serumproteomes of 40 patients and 40 controls were
investigated using two-dimensional gel electrophoresis (2-DE) and
matrix-assisted laser desorption ionization time-of-flight/time-offlight
mass spectrometry (MALDI-ToF/ToF MS). The novel
biomarker found was further validated using Western Blot.
Results: Three protein spots were found to be altered in patients
compared to controls. Among these acute phase proteins,
apolipoprotein H (ApoH, p = 0.00346) showed significant
overexpression in patients whilst apolipoprotein A-I (ApoA-I, p =
0.00365) and haptoglobin (p = 0.00307) were found down-regulated
in patients compared to controls. ApoA-I and haptoglobin were
previously found to be associated with SCZ. However to the best of
our knowledge, ApoH is a novel serum marker for SCZ. To validate
the result, western blotting with anti-ApoH to control and patient
serums (n = 8) which were randomly selected from the tested group.
As expected, a single specific band of molecular weight
approximately 38 kDa was detected in membrane probed with anti-
ApoH antibody in sera tested. In comparison, the expression level of
ApoH in patient’s serum is significantly higher than normal control
group (p < 0.0298). In order to double confirm the differential
expression of ApoH, the same experiment was repeated with the
pooled sera of normal and patient group. A similar trend of results
was obtained where patient group significantly showed the higher
expression level of ApoH protein as compared with the normal
control group (p < 0.0306).
Conclusions: These findings suggest that increased level of ApoH
might be associated with the pathology of SCZ. Hence ApoH serves
as novel biomarkers for SCZ as it was not reported elsewhere up-todate.

PP236 PAST HISTORY OF MENTAL DISORDERS
ASSOCIATES WITH LONGER PERIPHERAL BLOOD CELL
TELOMERES IN ELDERLY ADULTS: THE HELSINKI
BIRTH COHORT STUDY (HBCS)
K. Savolainen*(1), K. Räikkönen(1), L. Kananen(2,3), E.
Kajantie(4,5), I. Hovatta(2,3,6), M. Lahti(1), J. Eriksson(4,7,8,9,10)
1. Institute of Behavioural Sciences, University of Helsinki 2.
Research Programs Unit, Molecular Neurology, Biomedicum-
Helsinki, University of Helsinki 3. Department of Medical Genetics,
Haartman Institute, Faculty of Medicine, University of Helsinki 4.
Diabetes Prevention Unit, Department of Chronic Disease
Prevention, National Institution for Health and Welfare 5. Hospital
for Children and Adolescents, Helsinki University of Central
Hospital 6. Department of Mental Health and Substance Abuse
Services, National Institute for Health and Welfare 7. Folkhälsan
Research Centre 8. Unit of General Practice, Helsinki University of
Central Hospital 9. Vasa Central Hospital 10. Department of General
Practice and Primary Health Care, University of Helsinki
*katri.savolainen@helsinki.fi
Introduction: Accelerated telomere length (TL) shortening has
previously been linked with mental disorders including schizophrenia
and mood disorders. Mental disorders are also associated with early
mortality. Yet, it remains unclear if accelerated TL shortening
characterize patients who have diagnosed for mental disorders in the
past, and survived till older age.
Methodology: The participants were 61.5 (SD=2.9, Range=56.6-
69.8) year-old women (n=1051) and men (n=905) from the HBCS,
born between years 1934-1944. TL from peripheral blood cells was
measured using real-time quantitative PCR method. Individuals with
mental disorders (n=116) severe enough to warrant hospitalization
were identified from Finnish Hospital Discharge Register. The
average time from last mental disorder hospitalization to
measurement of TL was 12.9 (SD=8.9, Range=0.3-31.3) years.
Results: Participants hospitalized for any mental or substance use
disorders had longer TL than non-hospitalized controls (age and sex
controlled p-values

PP238 OVERALL EFFECT OF BDNF VAL66MET
POLYMORPHISM ON BODY MASS INDEX AND BIPOLAR
DISORDER
M. Rivera*(1), G. Hosang(1), S. Cohen-Woods(1), G. Breen(1), R.
Investigators(1), F. Tozzi(2), J. Perry(2), P. Muglia(2), C. Lewis(1),
I. Craig(1), J. Vincent(3), J. Strauss(3), P. McGuffin(1), A. Farmer(1)
1. MRC SGDP Centre, Institute of Psychiatry, King's College
London 2. GlaxoSmithKline Research and Development, Medical
Genetics, Clinical Pharmacology and Discovery Medicine 3.
Neurogenetics Section, Centre for Addiction and Mental Health,
Department of Psychiatry, University of Toronto
*margarita.rivera_sanchez@kcl.ac.uk
Introduction: Associations between body mass index (BMI) or
obesity and psychiatric disorders have been reported in numerous
studies. The BDNF Val66Met polymorphism has been associated
with depression and bipolar disorder, as well as obesity and BMI.
The aim of this study is to explore the genetic influence of the BDNF
Val66Met polymorphism in relation to BMI in a sample of bipolar
disorder cases and psychiatrically healthy controls.
Methodology: The sample is part of the Bipolar Association Case-
Control Study (BACC) and consists of approximately 1,000 bipolar
cases and 1,400 controls. ICD-10 bipolar diagnoses were made using
the SCAN interview. The controls were screened for lifetime absence
of any psychiatric disorders. The sample was genotyped for the
BDNF Val66Met polymorphism (rs6265). Participants’ weight and
height were used to calculate BMI, defined as weight (kilograms) /
height (metres) 2 .
Results: Linear regressions were performed to test for association
between BDNF Val66Met variant and BMI in the whole sample and
separatelyin the different clinical groups. We found an overall
association between this polymorphism and BMI in the whole
sample, mainly attributable to the control group.
Conclusions: We have investigated the influence of the BDNF
Val66Met variant on BMI in a large clinical sample of bipolar
patients and controls. There are two mainly findings, first this
polymorphism was significantly associated with bipolar disorder,
second the BDNF variant was significantly related to BMI. This is the
first study investigating the effect of the BDNF Val66Met
polymorphism on BMI within the context of bipolar disorder.
191
PP239 ASSOCIATION ANALYSES OF TUMOR NECROSIS
FACTOR ALPHA GENE POLYMORPHISMS WITH
OBSESSIVE-COMPULSIVE AND TIC DISORDERS
K. Emese*(1), N. Zsofia(1), K. Eszter(2), T. Zsanett(2), K.
Gergely(1), S. Maria(1)
1. Institute of Medical Chemistry, Molecular Biology and
Pathobiochemistry, Semmelweis University 2. Vadaskert Child and
Adolescent Psychiatric Clinic
*mesi10@gmail.com
Introduction: In a minority of cases, children are diagnosed with
Tourette syndrome (TS) and obsessive-compulsive disorder (OCD)
after streptococcal infections. The pro-inflammatory cytokine, tumor
necrosis factor alpha (TNF) is hypothesized to play a role in these
autoimmune processes. Therefore, the possible genetic vulnerability
of children with TS and OCD diagnoses were tested for TNF gene
promoter polymorphisms with possible effect on gene expression.
Methodology: A total of 214 children (male 80.6%, average age at
the onset of the disorder 10.3 ± 3.6) with main diagnosis of TS
(N=113) or OCD (N=101) participated in the case-control study. The
diagnoses were obtained by the DSM-IV criteria. The control sample
consisted of 273 healthy young adults (average age 22.1 ± 6.4). Both
groups were ethnically homogenous (Hungarian, Caucasian origin).
Tic and obsessive-compulsive symptoms were also assessed by the
MINI-kid (Mini-International Neuropsychiatric Interview, child
version) in an extended child psychiatry sample (N=338).
Polymorphisms of the TNF-alpha gene were the following: -238 A/G
(rs361525), -308 A/G (rs1800629), and -863 A/C (rs1800630). Chisquare
analyses were carried out for the main diagnoses vs control
group, as well as for tic and obsessive-compulsive symptom present
vs absent groups.
Results: The genetic association analyses of the main diagnostic
categories showed an increase of the -238 A-allele frequency in both
the TS and OCD groups compared to the control group. The -308 Aallele
frequency was decreased in the TS group (vs control group)
and in the tic-present group (vs tic absent group). No association was
found with the -863 A/C polymorphism.
Conclusions: The preliminary analyses of TNF gene promoter
polymorphisms in our child psychiatry sample suggest that the TNF -
238 A-allele might act as a risk (vulnerability) factor in the TS-OCD
spectrum and the -308 A-allele might act as a protective (resilience)
factor in Tourette syndrome.
This work was supported by Hungarian Scientific Research Fund
(OTKA) F67784 and CK80289.

PP240 NICOTINE DEPENDENCE AND DOPAMINE
METABOLISM ENZYME GENES
T. Shinkai*(1), H. Chen(1), K. Utsunomiya(1), K. Yamada(1), S.
Sakata(1,2), O. Ohmori(1,3), J. Nakamura(1)
1. University of Occupational and Environmental Health 2.
Sagamigaoka Hospital 3. Wakato Hospital
*shinkai@med.uoeh-u.ac.jp
Introduction: Cigarette smoking increases the risk of various health
problems, including cancer, cardiovascular and pulmonary disorders,
making smoking the leading cause of preventable death in the world.
Twin and family studies have indicated significant genetic
contributions to smoking behaviors. Although genetic associations to
nicotine dependence have been widely investigated, the relevance of
individual genetic variations for smoking behavior remains unknown.
The noteworthy candidate genes are involved in the dopamine
pathways for the brain reward system.
Methodology: We examined an association of polymorphisms at two
dopamine metabolism enzymes (i.e., tyrosine hydroxylase, dopamine
beta-hydroxylase) and their relation to nicotine dependence in a total
of nearly 700 healthy workers in a Japanese heavy industry company.
Smoking behavior was assessed by a questionnaire including
Fagerström Test for Nicotine Dependence (FTND) and Tobacco
Dependence Screener (TDS).
Results: Although our preliminary data does not suggest significant
associations with nicotine dependence, analysis with complete data
set is currently undergoing to clarify the relationship between the
dopamine system genes and nicotine dependence.
Conclusions: It is thought that dopamine is critically involved in
drug addiction processes. Scientific knowledge on dopamine system
accumulated in pharmacogenetic studies may lead to a solution to
prevent and to treat nicotine dependence.
192
PP241 ASSOCIATION STUDY BETWEEN VITAMIN D
RECEPTOR POLYMORPHISM AND ALZHEIMER’S
DISEASE
K. Yamada*(1), T. Shinkai(1), K. Utsunomiya(1), S. Sakata(1,2), H.
Chen(1), J. Nakamura(1)
1. University of Occupational and Environmental Health 2.
Sagamigaoka Hospital
*hokuto_no_ken_1225@yahoo.co.jp
Introduction: In the central nervous system (CNS), Vitamin D 3
plays a key role in neuroprotection against oxidative stress, calcium
homeostasis, and production of neurotrophins. The single nucleotide
polymorphisms (SNPs) in the vitamin D receptor (VDR) gene which
causes altered affinity to vitamin D3 may thus be related to
neurodegenerative diseases. Gezen-Aket al (2007) reported a positive
association between two SNPs in the VDR gene (ApaI: rs7975232
and TaqI: rs731236) and late-onset Alzheimer's disease (LOAD) in a
Turkish sample (104 LOAD cases and 109 controls). To our
knowledge, no Japanese study has conducted in terms of this
association.
Methodology: In the present study, we examined an association
between the above mentioned two SNPs and LOAD in a Japanese
sample (100 LOAD cases and 200 controls).
Results: Although our data does not suggest a robust association,
analysis with complete data set is currently undergoing to clarify the
relationship between the VDR gene and LOAD.
Conclusions: Our study provides evidence for a possible link
between LOAD and vitamin D.

PP242 ASSOCIATION STUDY BETWEEN A SINGLE
NUCLEOTIDE POLYMORPHISM IN ZNF804A GENE AND
ATTENTION DEFICIT HYPERACTIVITY DISORDER
X. Xu*(1), G. Breen(1), L. Luo(2), B. Sun(2), C. Chen(3, 4, 5), Y.
Huang(4, 5), Y. Wu(4, 5), P. Asherson(1)
1. MRC Social, Genetic and Developmental Psychiatry Centre,
Institute of Psychiatry, King's College London 2. School of
Medicine, King's College London 3. Department of Psychiatry,
Chang Gung Memorial Hospital 4. Chang Gung University School of
Medicine 5. Division of Mental Health & Drug Abuse Research,
National Health Research Institutes
*xiaohui.xu@kcl.ac.uk
Introduction: Attention-deficit hyperactivity disorder (ADHD) is
one of the most frequent and heritable childhood behavioural
disorders characterised by age inappropriate levels of hyperactivity,
impulsivity and inattentiveness. There was evidence showing a strong
genetic contribution to ADHD in adoption, family and twin study.
Polymorphic variants in several genes involved in regulation of
dopamine and related neurotransmitter pathways are reported to be
associated with ADHD. The most investigated candidate genes were
DAT1, DRD4, COMT, MAOA and DBH. Recently genome-wide
association (GWA) study has been conducted on ADHD and
psychiatric disorders. ADHD and psychiatric disorders share many
features clinically. Balog et al. (2010) investigated the relationship
between single nucleotide polymorphism (SNP) rs1344706 in
ZNF804A and attention in 200 healthy volunteers. Their study found
a significant association with the executive control network of
attention: the A/A genotype and the A-allele were associated with
increased reaction time. One recent study by Landaas et al (2011)
examined six SNPs in CACNA1C, ANK3, MYO5B, TSPAN8 and
ZNF804A genes in adult ADHD, and concluded that the six SNPs
including rs1344706 in ZNF804A with strong evidence of association
in bipolar (BD) GWA studies seem unlikely shared risk variants
between ADHD and BD. In this study we examine the role of
rs1344706 polymorphism in two clinical family-based ADHD
samples from the UK and Taiwan.
Methodology: To investigate the association between the
polymorphism (rs1344706) in ZNF804A and ADHD, two family
samples of ADHD probands from the United Kingdom (n = 180) and
Taiwan (n = 212) were genotyped using a TaqMan SNP genotyping
assay on a 7900HT sequence detection system (Applied Biosystems)
and analysed using within-family transmission disequilibrium test
(TDT).
Results: No significant associations were found between rs1344706
polymorphism and ADHD in either of the family samples from
Taiwan (P = 0.91) and UK (P = 0.43). Even combining the two
family datasets together the A allele of rs1344706 SNP was still not
significantly over-transmitted to the affected probands (P = 0.50).
Conclusions: In this study we used family-based ADHD data in the
UK and Taiwanese population to test for an association between
rs1344706 SNP in ZNF804A gene and ADHD. Our results showed
that the rs1344706 SNP with strong evidence of association in bipolar
disorder (BD) GWA studies does not have significant association in
ADHD for UK and Taiwanese population.
193
PP243 REPLICATION OF CNTNAP2 IN A LONGITUDINAL
SAMPLE WITH AND WITHOUT LANGUAGE IMPAIRMENT
K. Mueller*(1), J. Murray(2), B. Tomblin(1)
1. University of Iowa, Department of Communication Sciences and
Disorders 2. University of Iowa, Department of Pediatrics
*kathryn-mueller@uiowa.edu
Introduction: Specific Language Impairment (SLI [MIM 602081])
is a relatively common developmental disorder characterized by
difficulty in acquiring language in the absence of cognitive or sensory
impairments, and despite adequate experience and educational
opportunities (Tomblin, et al., 1996). The disorder is associated with
deficits in academic achievement, elevated rates of unemployment,
and impairments in socio-emotional development. Although there is a
significant heritable component, molecular studies have been slow to
identify genes involved in the neurobiology of language
development, and little research exists on common genetic variants
that contribute to individual differences in language ability. One
candidate, CNTNAP2, has been associated with language
impairments both in children with SLI and in children with autism
(Alarcón, et al., 2008; Vernes, et al., 2008). CNTNAP2 encodes a
neurexin, a transmembrane protein that mediates cell–cell
interactions in the developing nervous system. The gene is highly
expressed in the cerebral cortex. In addition, CNTNAP2 is in the
same neurobiological pathway as FOXP2, a gene that has been welldocumented
in the development of speech and language. Following
findings from Vernes et al. (2008) and Whitehouse et al. (2011), we
hypothesized that variants in the gene would also influence a broader
range of language abilities in a large epidemiological sample of
children with and without language impairment.
Methodology: Participants (n=604) and their families were recruited
in Iowa and Illinois from a longitudinal study of language
development and disorders (Child Language Research Centre, The
University of Iowa). An initial pool of participants (n=7,218) was
screened in kindergarten as part of a cross-sectional epidemiological
study. A stratified-cluster sampling method was used to invite
individuals to participate in the diagnostic phase of the study.
Children who failed the language screening test, plus a random
sample who passed (~33%), were administered a more
comprehensive set of language and cognitive assessments as a
diagnostic battery for SLI (n=2,009). Children completed five
language subtests from the Test of Oral Language Development-2 P:
Picture Vocabulary, Oral Vocabulary, Grammatic Understanding,
Sentence Imitation, and Grammatic Completion, as well as the test of
Word Articulation (Newcomer & Hammill, 1988). Narrative
comprehension and production were assessed using the Listening to
Paragraphs subtest of the CELF-III (Semel, et al., 1987) and a spoken
story generation task by Catts & Fey (1998). Scores were converted
into composite ability scores for the present study. Children with SLI
were defined as those whose standardized language scores fell 1.15
SD below the mean for their age. Because of the way the sample was
ascertained, phenotype data followed a normal pattern of distribution.
DNA was obtained from blood, buccal swabs, and saliva for 601 of
the probands, their parents and siblings (total n=1,482). Samples
were genotyped using Taqman Pre-designed Genotyping Assays
under standard reaction conditions (Applied Biosystems, Foster City,
CA). Potential confounds arising from population admixture were
eliminated by restricting analysis to the Caucasian sample only.
Allelic variation was determined via the Sequence Detection Systems
2.2 software (Applied Biosystems). PLINK was used to identify
Mendelian errors, estimate allele frequencies, test for Hardy-
Weinberg equilibrium, and perform association analyses.
Results: Significant association was found for a single SNP,
rs2710117, across a range of language abilities, including language
diagnosis (LDIAG, p

PP244 ETHICAL CONCERNS ABOUT PSYCHIATRIC
GENETIC STUDIES: ITEM FUNCTIONING AND BIAS OF
QUESTIONNAIRE ABOUT GENETIC RISK
M. Hipolito*(1), M. Malik(1), W. Lawson(1), J. Nurnberger, Jr(2),
E. Nwulia(1)
1. Howard University 2. Indiana University
*mhipolito@howard.edu
Introduction: High level of perceived concerns surrounding
unethical use of genetic data could hinder participation in psychiatric
genetic studies. However, there is a paucity of questionnaires for
examination of ethical concerns to participation in psychiatric genetic
studies. Of the few available, robustness to differential ethnic bias
equating for severity of concerns have not been demonstrated. We
investigated the quality of Questionnaire on Genetic Research (QGR)
for measuring the extent of perceived concern in a population with
Bipolar disorder, and examined the robustness of the response items
to differential bias by ethnic status.
Methodology: Six questions measured the degree of concerns about
negative consequences from psychiatric genetic studies in the QGR.
Each question has 5 response categories corresponding to increasing
degree of concern, ranging from “not at all” concerned to “very
concerned.” We applied polytomous item response models (IRM)
with latent constructs for analysis of complete responses by
respondents.
Results: Most items of the QGR provided reliable measure of the
extent of concerns. The instrument also validated the findings of
greater concern about genetic studies among American Blacks
compared to Whites. Item bias was observed for concerns about
racism, procreation and privacy, but adjusting for these latter 3 items
in a sensitivity analysis did not substantially change the association
between Blacks and level of concern.
Conclusions: For the most part, the QGR is a reliable measure of the
extent of perceived concern, based on response patterns to its six
items. However, cautious interpretations of some items are warranted
when the ethnicity of the study sample is diverse, due to vulnerability
to response bias.
194
PP245 ALZHEIMER’S DISEASE DIAGNOSTICS BASED ON
MULTI-MODAL DATA SETS
M. Sattlecker*(1), K. Lunnon(1), P. Proitsi(1), A. Stewart(3), S.
Williams(3), G. Coppola(3), D. Geschwind(3), A. Hodges(1,2), S.
Lovestone(1,2), R. Dobson(1)
1. NIHR Biomedical Research Centre for Mental Health, South
London and Maudsley NHS Foundation Trust & Institute of
Psychiatry, Kings College London 2. MRC Centre for
Neurodegeneration, King's College London 3. SomaLogic, Inc. 2945
Wilderness Place
*martina.sattlecker@kcl.ac.uk
Introduction: There is a need for non-invasive biomarkers in
Alzheimer's disease (AD), not only to diagnose the disease state but
also for stratification and experimental medicine as well as providing
an insight into disease pathogenesis. In this study we focus on the
potential of blood plasma protein and RNA levels as markers for AD
but describe the added benefit of including other measures such as
ApoE4 dosage and sMRI measures using data derived from the EU
funded AddNeuroMed Alzheimer's biomarker project.
Methodology: The AddNeuroMed project has produced a rich
variety of datasets including peripheral blood whole transcriptome
RNA measures, 822 protein plasma measures (with SomaLogic, US
Biotech), sMRI, whole genome SNP genotypesand a rich set of
clinical phenotypes that includes rates of cognitive decline (MMSE,
CDR and ADAS-Cog). These data are available on over 300 patients
comprising AD cases, normal elderly controls and as well as patients
suffering from mild cognitive impairment (MCI), of which
approximately half converted to AD within two years of baseline
measures. We developedpredictive models that included, but went
beyond standard diagnostic comparisons, identifying predictive
models of prodromal AD and rate of decline using the multi-modal
datasets available
Results: We found that the combination of different data types
drastically improves the predictive power of models built for AD. A
model integrating gene expression and sMRI yielded an accuracy of
81% for controls and 100% for MCI cases (controls vs. MCI), 76%
for controls and 83% for AD samples (controls vs. AD), and 92% for
MCI samples and 72% for AD samples (MCI vs. AD). Furthermore
we found that regression models using protein plasma measurements
demonstrate high potential for predicting the rate of decline in AD
patients.
Conclusions: This study demonstrated that classification and
regression models integrating multi-modal data sets resulted in
improved accuracy in comparison to models using single data types.
Such models show potential for the future application of non-invasive
biomarkers in AD clinical trials and the clinic. However, there are
many considerations to be aware of and explored. These include
identifying biomarkers that are specific and reflect the many routes to
the same pathology.

PP246 PURINERGIC RECEPTOR P2RX7 GENE
POLYMORPHISMS: ASSOCIATION STUDY WITH
DEPRESSIVE SYMPTOMS AND MOLECULAR GENETIC
ANALYSIS
Z. Nemoda*(1), O. Abdul Rahman(1), A. Vereczkei(1), A.
Somogyi(2), G. Faludi(3), M. Sasvari-Szekely(1)
1. Department of Medical Chemistry, Molecular Biology and
Pathobiochemistry, Semmelweis University 2. 2nd Department of
Internal Medicine, Semmelweis University 3. Department of
Psychiatry, Kútvölgyi Clinical Centre, Semmelweis University
*zsofia.nemoda@eok.sote.hu
Introduction: The Gln460Arg polymorphism (rs2230912) of the
P2RX7 (purinergic receptor P2X, ligand-gated ion channel, 7) gene
has been indicated in major depressive and bipolar disorder (MDD,
BPD). In our previous studies we reported increased anxiety and
depression scores assessed by the Hospital Anxiety and Depression
Scale (HADS) in patients carrying the 460Arg-variant (G-allele) in
psychiatric and diabetic patient samples. However, recently published
data did not support the role of this P2RX7 A/G single nucleotide
polymorphism (SNP). Therefore, we analyzed SNPs in the 3’
untranslated region (UTR) of the P2RX7 gene which might affect
putative miRNA binding and are in linkage with the Gln460Arg.
Methodology: The in silico search for polymorphisms in putative
microRNA target sites was carried out by the PolymiRTS
(http://compbio.utmem.edu/miRSNP/) and the Patrocles
(http://www.patrocles.org/) databases. Three A/C SNPs were
identified as possible candidates in the P2RX7 3’ UTR region at
positions 2164-2166, 689 bp downstream from the Gln460Arg. Since
there was only one source of information about the 2166 A/C SNP
(rs28969482) indicating 5% minor allele frequency, but the
sequencing of 22 random DNA samples did not show polymorphic
site in our patient population, only the 2164 A/C SNP (rs1653625)
and the 2165 A/C SNP (rs1718106) were analyzed. These two SNPs
were genotyped by RFLP technique using primers with mismatches
to create restriction enzyme cleavage sites. The Haploview program
indicated high linkage among these SNPs and Gln460Arg
(rs2230912). In the genetic association analyses the depressive and
anxiety scales of the HADS questionnaire was used both in the
psychiatric patient sample (N=154, women 74.7%, average age
47.9±10.8) and in the diabetic patient sample (N=246, women 50.4%,
average age 58.2±13.3). In the molecular analyses HEK cells were
transfected by the pMIR vector constructs containing the P2RX7 3’
UTR downstream of the luciferase gene.
Results: The 2164 A/C showed an association with the severity
scores of anxiety and depressive symptoms in both populations:
carrying the 2164 A-allele showed a step-wise increase in the 3
genotype groups (depressed patients: anxiety: p=0.017, depression:
p

PHARMACOGENOMICS
PP248 MESOLIMBIC HYPODOPAMINERGIC FUNCTION A
POTENTIAL NUTRIGENOMIC THERAPEUTIC TARGET
FOR DRUG CRAVING AND RELAPSE
K. Blum*(1), M. Miller(2), K. Perrine(3), Y. Liu(1), J. Gordano(4),
M. Oscar-Berman(5)
1. University of Florida 2. LifeStream, Inc 3. Cornel University 4. G
&G Holistic Addiction Treatment Center 5. Boston University
*drd2gene@aol.com
Introduction: Dopamine plays an important role in drug seeking
behavior. It is well established that Substance Use Disorder (SUD) is
inheritable and runs in families. Hypodopaminergic function is a
major culprit in multiple addictive behaviors and is regulated by a
number of reward genes.
Methodology: In this study we evaluated a known natural
Dopaminergic agonist KB220IV along with oral[KB220] variants
directed to overcoming hypodopaminergic function by assessing pre
and post chronic symptoms and gene testing.
Results: In our first experiment we found a significant reduction of
chronic symptoms as measured by Chronic Abstinence Symptom
Severity [CASS] Scale for both IV and oral compared to only oral
administration. Specifically, the IV and oral group did significantly
better than the oral only group over the first week as well as over the
30 day period. In the second experiment consisting of 129 subjects
receiving both IV and orals three factors with eigenvalues greater
than one were extracted for the baseline CASS variables. Three
scales were constructed based on this factor analysis: Emotion,
Somatic, and Cognitive. Paired sample t-tests between the pretreatment
scales and the post-treatment scales were calculated. All
three scales showed significant declines (p=.00001) from pre- to
post-treatment: t=19.1 for Emotion, t=16.1 for Somatic, and t=14.9
for Cognitive. In a two year follow-up on 23 subjects who underwent
KB220IV therapy (at least five IV treatments over a 7 day period)
plus orals for at least 30days: 21 (91%) were sober at 6 months with
19 (82%) having no relapse 19 (82%) were sober at one -year with 18
(78%) having no relapse 21 (91%) were sober at two-years post –
treatment with 16 (70%) having no relapse. We also found that in two
independent treatment centers ( heroin addicts in China
Psychistimulant abusers in Florida) that 100% of all subjects tested
for 6 polymorphic genes involved in dopaminergic neurotransmission
had at least one risk allele and 74% of these subjects had moderate to
high genetic risk as measured by the Genetic Addiction Risk Score
(GARS) test. Moreover, through fMRI we are also showing
significant dopaminergic activation of a number of dopaminergic
brain regions with KB220Z compared to placebo.
Conclusions: While awaiting additional required research, we
cautiously propose that KB220IV therapy (a putative dopaminergic
agonist) may provide early important therapeutic outcomes in
residential treatment programs. These data agree with our recent
KB220Z neuroimaging studies showing qEEG regulation of the
cingulate gyrus abnormal dysynchronization in protracted abstinent
psychostimulant addicts especially in DRD2 A1 allele carriers. We
have published earlier showing an increase in alpha activity and an
increase in low beta bands using KB220Z. These results suggest that
following extensive further investigation KB220Z and KB220IV may
be important therapeutic agents to combat drug craving behavior and
potentially relapse by targeting hypodopaminergic deficits
196
PP249 CORRELATION BETWEEN AMPLIFIABLE HUMAN
SALIVA-DERIVED DNA AND AFFYMETRIX ® DMET
ARRAY GENOTYPING CALL RATE IN PATIENTS WITH
SEVERE PSYCHIATRIC DISORDERS
K. Nelson*(1), E. Ehli(1, 2), P. Huizenga(1), T. Soundy(2), G.
Davies(1, 2), Y. Hu(1)
1. Avera Institute for Human Behavioral Genetics, Avera McKennan
Hospital and University Health Center 2. Department of Psychiatry,
University of South Dakota, Sanford School of Medicine
*kelly.nelson@avera.org
Introduction: Affymetrix ® DMET TM (drug metabolism enzymes and
transporters) array is the first assay to offer a comprehensive
representation of known pharmacokinetic markers and enables fast
discovery and measurement of genetic variation associated with drug
response. Human saliva is an important source for DNA as it is a
painless, convenient, and inexpensive collection method. There is
concern, however, of point source microbial contamination inherent
in the human saliva and how it may interfere with array genotyping
call rates (a critical quality control standard). To date, there are no
such reports demonstrating the effect of DNA derived from human
saliva on the DMET array genotyping call rates.
Methodology: Saliva samples (n=42) were collected from patients
with mental disorders at the South Dakota Developmental Center.
After genomic DNA extraction, we used a commercially available
RNase P kit to identify the percentage of amplifiable human DNA in
each sample. These samples were processed on DMET
arrays following the manufacturer's protocol. A sample subset (n=7)
was also processed on arrays at varying concentrations to determine
the effect DNA concentration had on genotyping call rates. All
samples were analyzed following the manufacturer's
instructions using DMET console software with Fixed and Dynamic
Genotype Boundary settings.
Results: Genomic samples containing >28.1% of amplifiable human
DNA passed the genotyping call rate threshold of 98% when
analyzed by DMET console software with Dynamic Genotype
Boundaries. When analyzed using DMET console software with
Fixed Genotype Boundaries, 82.4% of saliva samples containing
>41.6% of amplifiable human DNA passed the genotyping call rate
threshold. Overall, a higher percent of amplifiable human
DNA present in the saliva sample had a correspondingly higher
genotyping call rate regardless of which Boundary analysis
setting was utilized. Increasing the concentration of the extracted
saliva-derived DNA prior to DMET use did not significantly
(p>0.05) improve the genotyping call rate. We believe this was due
in part to the increasing ratio of competing microbial DNA remaining
in the saliva derived DNA sample.
Conclusions: Currently, we are genotyping blood-derived DNA from
the same individuals in this study to compare saliva and bloodderived
DNA performance on DMET arrays. While blood-derived
DNA continues to be the standard, this study may provide
a screening protocol and thus a potential improvement to the
genotyping call rate for human saliva DNA samples as a source
material for DMET arrays.

PP250 INFLUENCE OF TPH2, DAOA AND BDNF VARIANTS
ON DIAGNOSIS AND RESPONSE TO TREATMENT IN
PATIENTS WITH MAJOR DEPRESSION, BIPOLAR
DISORDER AND SCHIZOPHRENIA
A. Chiesa(1), C. Pae(2,3), D. De Ronchi(1), A. Serretti*(1)
1. Istitute of Psychiatry, University of Bologna 2. Catholic University
of Korea College of Medicine 3. Department of Psychiatry and
Behavioral Sciences
*albertopnl@yahoo.it
Introduction: Current evidence suggests that several genes including
the tryptophan hydroxylase 2 (TPH2), the D-amino acid oxidase
activator (DAOA) and the brain derived neurotrophic factor (BDNF)
could be involved in the etiology and response to treatment of several
psychiatric disorders. Accordingly, we aimed to investigate whether
some SNPs within these genes, including rs4570625, rs10748185,
rs11179027, rs1386498, rs4469933, rs17110747 (TPH2), rs3916966,
rs3916967, rs2391191, rs3916968, rs7139958, rs9558571, rs778293
(DAOA), rs2030324, rs7103873, rs10835210, rs11030101 and rs6265
(BDNF) could be associated with major depression (MD), bipolar
disorder (BD) and schizophrenia and whether they could predict
clinical outcomes in Korean in-patients treated with antidepressants,
mood stabilizers and antipsychotics respectively.
Methodology: One hundred forty five patients with MD, 132 patients
with BD, 221 patients with schizophrenia and 170 psychiatrically
healthy controls were genotyped for the SNPs mentioned above.
Baseline and final clinical measures, including MADRS, YMRS and
PANSS scores for patients with MD, BD and schizophrenia
respectively were recorded.
Results: Rs10835210 CA and rs11030101 AT genotype frequencies
were higher in BD and schizophrenia patients than in healthy and
MD subjects. In patients with MD, rs4570625-rs10748185 G-A
haplotype was associated with higher endpoint MADRS severity.
Additionally, Rs7139958 AA and rs9558571 TT genotypes as well as
rs7139958 A and rs9558571 T alleles were associated with higher
baseline PANSS positive subscale scores in patients with
schizophrenia.
Conclusions: Some associations have been observed between genetic
variants under investigation and specific psychiatric disorders and
clinical outcomes. However, current evidence is far from being
conclusive and further replications are required.
197
PP251 A PRELIMINARY INVESTIGATION OF CREB1,
PTGS2, GRIK4 AND GNB3 POLYMORPHISMS ON
TREATMENT RESISTANCE IN MAJOR DEPRESSION
A. Serretti*(1), A. Chiesa(1), C. Crisafulli(2), R. Calati(1), I.
Massat(3), S. Linotte(4), S. Kasper(5), I. Antonijevic(6), C.
Forray(6), L. Snyder(6), J. Bollen(7), J. Zohar(8), D. De Ronchi(1),
D. Souery(9), J. Mendlewicz(4)
1. Institute of Psychiatry, University of Bologna 2. University of
Messina 3. Neurological Experimental Laboratory 4. Universite´
Libre de Bruxelles 5. Department of Psychiatry and Psychotherapy,
Medical University 6. Translational Research, Lundbeck Research 7.
Sint-Truiden, Psychiatric Center 8. Chaim Sheba Medical Center 9.
Laboratoire de Psychologie Medicale, Universite´ Libre de Bruxelles
and Psy Pluriel, Centre Europe´en de Psychologie Medicale
*albertopnl@yahoo.it
Introduction: Several genes including those coding for the
transcription factor cyclic adenosine monophosphate response
element binding (CREB1) protein, the prostaglandin-endoperoxide
synthase enzyme 2 (PTGS2), the glutamate ionotropic kainate 4
receptor (GRIK4) and the guanine nucleotide binding protein beta
polypeptide 3 (GNB3) have been repeatedly involved in the aetiology
and response to treatments of major depression (MD). Accordingly,
The aim of the present paper is to investigate whether a set of single
nucleotide polymorphisms (SNPs) within CREB1 (rs2709376,
rs2253206, rs7569963, rs7594560, rs4675690),PTGS2(rs4648276,
rs2066826 and rs689466), GRIK4 (rs1954787) and GNB3 (rs5443)
geneswas associated with MD as well with antidepressant response,
remission and treatment resistance.
Methodology: 194 MD patients and 76 healthy controls treated with
antidepressants at adequate doses for at least 4 weeks were genotyped
for CREB1, PTGS2, GRIK4and GNB3SNPs. Response, remission and
treatment resistance were recorded.
Results: A allele of rs7569963 as well as rs2253206-rs7569963 A-A
and rs7569963-rs4675690 A-C haplotypes in CREB1 were
significantly associated with treatment resistance. No significant
association was observed between any of the remaining genotypic,
allelic and haplotypic variants under investigation and outcomes of
interest.
Conclusions: Some genetic polymorphisms in CREB1 could
influence treatment resistance to antidepressants. On the other hand,
there is no evidence suggesting any association between CREB1,
PTGS2, GRIK4and GNB3andtreatment response or remission and
with MD. However, on account of the several limitations of the
present study including a relatively small sample size and the
incomplete coverage of genes under investigation, further research is
needed.

PP252 PHARMACOGENETICS: FROM RESEARCH TO
CLINICAL PRACTICE-COST-UTILITY ANALYSIS
P. Olgiati*(1), A. Serretti(1), E. Bajo(2), M. Bigelli(2)
1. Department of Psychiatry - University of Bologna 2. Department
of Management and Economy - University of Bologna
*polgiati@hotmail.com
Introduction: Pharmacogenetics may represent a valuable tool to
improve drug choice by identifying likely responders a priori,
however the exact benefit in routine activity has been scarcely
investigated.We performed a cost-utility analysis of incorporating 5-
HTTLPR genetic test in antidepressant treatment selection.
Methodology: We implemented a theoretical analytic model to
compare the cost-utility of two treatment strategies for major
depressive disorder (MDD) within a 12-weeks trial: A. SSRI
monotherapy B. alternative administration of serotonergic or
noradrenergic antidepressants under guidance from 5-HTTLPR
polymorphism. Patients with the long-allele, who are more likely to
respond to SSRI treatment, received citalopram whereas s-s allele
carriers were treated with noradrenergic dopaminergic agent
bupropion. The model was based on Italian Mental Health setting.
Costs (international dollars of 2010) were derived from World Health
Organization CHOICE project and Italian official sources. The effect
size of 5-HTTLPR test was estimated from a meta-analysis of
pharmacogenetic trials.
Results: The use of genetic test increased remitters by 5%, with an
estimated gain of 0.07 Quality-Adjusted Life Weeks. This projected
ICER to $ 3,269 (largely above cost-effectiveness threshold), but
only for the worse case scenario, while the distribution was largely
below threshold. Sensitivity analysis demonstrated the strongest
impact of genetic test cost on ICER. Quality of life (HRQL) assigned
to untreated depression and 5-HTTLPR effect size were less
important contributors. Modeling variations in these parameters,
pharmacogenetic approach became cost-effective. Under base-case
conditions genetic test should cost $75 or less to drop below costeffectiveness
threshold. In severe depression with low HRQL the cost
of genetic test could raise to $270.
Conclusions: To date performing a pharmacogenetic test before
starting antidepressant treatment may be moderately cost-effective in
selected groups of patients with severe and disabling MDD.
Pharmacogenetics may become available for clinical practice if
prediction power of tests is improved and costs drop to $50 - $100.
198
PP253 ASSOCIATION BETWEEN COMT POLYMORPHISMS
AND CLINICAL RESPONSE TO RISPERIDONE
TREATMENT: A PHARMACOGENETIC STUDY
Q. Zhao(1,2,3), B. Liu(1,2,3), J. Zhang(1,2,3), L. Wang(1,2,3), X.
Li(1,2,3), Y. Wang(1,2,3), L. He(1,2,3), G. He(1,2,3)
1. Bio-X Center, Key Laboratory for the Genetics of Developmental
and Neuropsychiatric Disorders (Ministry of Education), Shanghai
Jiao Tong University 2. Institutes of Biomedical Sciences, Fudan
University, 138 Yixueyuan Road 3. Institute for Nutritional Sciences,
Shanghai Institutes of Biological Sciences, Chinese Academy of
Sciences, 320 Yueyang Road
Introduction: Catechol-O-methyl transferase (COMT) is one of the
genes which confer susceptibility to schizophrenia, because of its role
in neurotransmitter metabolism and its location in the high risk
schizophrenia related region 22q11. Recent studies also found that
COMT functional polymorphisms influenced individual response to
anti-psychotic medication. Our aim in this study was to explore the
influence of COMT polymorphisms on pharmaceutical response to
risperidone in the Chinese population.
Methodology: 130 Chinese schizophrenia patients (85 females) were
enrolled in the study. Clinical efficacy was determined using Brief
Psychiatric Rating Scores (BPRS). We genotyped 10 single
nucleotide polymorphisms (SNPs) of COMT in our patients and reexamined
them for association with changes in BPRS scores after 8
weeks of riperidone monotherapy. Written informed consent was
obtained from either the participants or the participants' legal
representatives after the research aims and procedures were fully
explained. The study protocol was reviewed and approved by the
Shanghai Ethical Committee of Human Genetic Resources.
Results: Statistical analysis revealed an association between an
upstream COMT SNP, rs9606186 and scores reduction of BPRS in
all patients and male subgroup, but not in female subgroup (Allele
analysis: p=0.055 for all, p=0.012 for male Genotype analysis:
p=0.046 for all, p=0.020 for male, uncorrected). Haplotype analysis
showed a highly significant association between COMT SNP
haplotypes and drug efficiency in our patient sample (p

PP254 GENOME-WIDE ASSOCIATION MAPPING OF LOCI
FOR ANTIPSYCHOTIC-INDUCED EXTRAPYRAMIDAL
SYMPTOMS IN MICE
J. Crowley*(1,2), Y. Kim(2), C. Quackenbush(2), A. Pratt(2), D.
Adkins(3), E. van den Oord(3,4), M. Bogue(5), H. McLeod(1), P.
Sullivan(2,6)
1. Institute for Pharmacogenomics and Individualized Therapy 2.
Department of Genetics 3. Center for Biomarker Research and
Personalized Medicine 4. Virginia Institute for Psychiatric and
Behavioral Genetics 5. The Jackson Laboratory 6. Department of
Psychiatry
*crowley@unc.edu
Introduction: Tardive dyskinesia (TD) is a debilitating,
unpredictable and often irreversible side effect resulting from chronic
treatment with a typical antipsychotic agent, such as haloperidol. It is
characterized by repetitive, involuntary, purposeless movements
primarily of the orofacial region. Human pharmacogenomic studies
of TD are needed to allow personalized treatment, but have been
underpowered by the relatively small number of patient samples
available.
Methodology: Therefore, we used a validated mouse model of TD
(vacuous chewing movements, VCMs) for a systems genetics
analysis geared toward detecting genetic predictors of TD in human
patients. Previous work from our laboratory has shown that
susceptibility to chronic haloperidol-induced VCMs is a highly
heritable trait in mice, under human-like steady state drug levels. In
the current study, phenotypic data from 27 inbred strains chronically
treated with haloperidol were subject to a comprehensive genomic
analysis involving 426,493 SNPs, 4,047 CNVs, brain gene
expression, along with gene network and bioinformatic analysis.
Results: Our results identified ~50 genes that we expect to have high
prior probabilities for association with haloperidol-induced TD, most
of which have never been tested for association with human TD. For
example, among our top hits were two glutamate receptors (Grin1,
Grin2a), a regulator of brain development (Zic4) and an indirect
target of haloperidol (Drd1a) that has not been as well studied as the
direct target, Drd2.
Conclusions: Not only is 50 genes a manageable number for
candidate-gene pharmacogenetic studies in human patients, but it also
provides a logical rationale for focusing on just a small fraction
(0.2%) of the genomic search space, reducing the multiple testing
penalty 500-fold.
199
PP255 RELAXIN POLYMORPHISMS ASSOCIATED WITH
METABOLIC DISTURBANCE IN PATIENTS TREATED
WITH ANTIPSYCHOTICS
M. Arranz*(1), O. Skrobot(2), V. Kay(3), J. de Leon(4), A.
Blakemore(5), J. Munro(6)
1. Institute of psychiatry-King's College London 2. Institute of
Clinical Neurosciences-University of Bristol 3. Insitute of
Neurology-UCL 4. University of Kentucky 5. Imperial College 6.
Optimal Medicine
*maria.arranz@kcl.ac.uk
Introduction: People with schizophrenia have an increased risk of
metabolic syndrome, with consequent elevated morbidity and
mortality largely due to cardiovascular disease. Metabolic disorders
comprise obesity, dyslipidemia and elevated levels of triglycerides,
hypertension and disturbed insulin and glucose metabolism.The
elevated risk of metabolic syndrome in individuals suffering from
schizophrenia is believed to be multi-factorial, related to a genetic
predisposition, lifestyle characteristics and treatment with
antipsychotic medications. Relaxin 3 (RLN3, also known as INSL7)
is a recently identified member of the insulin/relaxin superfamily that
plays a role in the regulation of appetite and body weight
control.RLN3 stimulates relaxin-3 receptor 1 (relaxin/insulin-like
family peptide receptor 3, RXFP3) and relaxin receptor 2
(relaxin/insulin-like family peptide receptor 4, RXFP4).
Methodology: We have investigated the role of ten polymorphisms
in these genes (RLN3 rs12327666, rs1982632, and rs7249702,
RLN3R1 rs42868, rs6861957, rs7702361, and rs35399, and RLN3R2
rs11264422, rs1018730and rs12124383) in the occurrence of
metabolic syndrome phenotypes (obesity, diabetes,
hypercholesterolemia, hypertrigyceridemia, and hypertension) in a
cross-sectional cohort of 419 US Caucasian patients treated with
antipsychotic drugs.
Results: We found several associations between relaxin
polymorphisms and hypecholesterolemia (p

PP256 A MULTIDISCIPLINARY PHARMACOGENOMIC
TREATMENT APPROACH TO REDUCE MEDICATION
BURDEN AND IMPROVE SUBJECT OUTCOMES IN A
RURAL DEVELOPMENTAL CENTER
K. Bohlen*(1,2), B. Bradley(3), E. Kutscher(3,4,5), T. Soundy(3,4),
E. Ehli(1,2), Y. Hu(1,2), G. Davies(1,2,3,4,5)
1. Avera Research Inst 2. Avera Inst for Human Behavioral Genetics
3. Avera Behavioral Health Ctr 4. Univ of South Dakota Department
of Psychiatry 5. South Dakota State Univ
*krista.bohlen@avera.org
Introduction: Saliva and blood samples were collected from
residents at a developmental center in South Dakota. The
samples were genotyped using the Affymetrix Drug Metabolism
Enzyme and Transporter (DMET) array. In addition, variable
number tandem repeats (VNT-R) in various psychiatric candidate
genes were also genotyped to assess subject pharmacogenomics
(Avera Health IRB 2009.053). Residents of this center suffer from
psychiatric disorders, mental retardation, and other debilitating
syndromes. The aim of this project is to improve patient outcomes
through treatment regimens based on pharmacogenomic analysis.
Methodology: This non-randomized, retrospective and prospective
comparison, proof-in-concept study utilized the DMET array which
analyzes 1,936 drug metabolism markers and transporters on
225 genes. A multidisciplinary team consisting of a psychiatrist,
pharmacists, a medical geneticist, and genetics lab scientists
collaborated on this project to provide a database for analysis of
DMET SNP results. The pharmacists and psychiatrist evaluated the
current medication regimens, past medications and effects, DSM IV
axes, AIMS scores, vital signs, and laboratory values for clinical
recommendations guided by pharmacogenomic results. The primary
polymorphisms analyzed were in CYP 450 enzymes including
CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and
CYP3A4. Additional analyses of a SNP in COMT, the 5HTTLPR
polymorphism in SERT, and DRD4 48-bp VNT-R in exon 3 were
also evaluated. The medical geneticist and lab staff designed primers
for PCR analysis to clarify ambiguous allele calls by the DMET array
and provide confirmatory results. Inconclusive results due to
unknown alleles resulted in no recommendation given. The
medications were evaluated in regards to the genomic results and
resultant enzyme function. A concise recommendation document is
provided to the treatment team which consists of drug-drug
interactions, pharmacogenetic considerations, therapeutic duplication,
drug monitoring, and other considerations (including
pharmacoeconomic implications).
Results: Fourty-two buccal-derived DNA and blood-derived DNA
have been run on the DMET array. Using the genetic data, a
personalized approach to medication management has been analyzed
in order to make clinical recommendations. The treatment team has
the discretion as to which recommendations to implement or
disregard. The first recommendations were given in February 2011.
For example, one of the patients is a CYP1A2 fast metabolizer
(inducible) who is on olanzapine. In a group of 10 patients, 4 are fast
(inducible) metabolizers for CYP1A2. In that same group, 1 is a poor
metabolizer for CYP2D6, 4 are intermediate, and 5 are normal.
The patients will be assessed at six months following the treatment
team recommendations. Any of those
recommendations implemented will be evaluated for impact on the
patient's outcomes as well as degree of implementation.
Conclusions: The multidisciplinary team approach has provided
insight from the psychiatrist, evaluation of pharmacogenomic results
by the pharmacists, and expertise from the genetics lab staff. We
hope to impact patients' lives by lessening the treatment burden,
decreasing adverse effects, and ultimately improving patient
outcomes through personalized medicine.
200
PP257 ANALYSIS OF 34 CANDIDATE GENES IN
BUPROPION AND PLACEBO REMISSION
A. Tiwari*(1), A. Yeo(2), M. Chiano(2), F. Tozzi(3), G. Sajeev(1),
C. Zai(1), T. Arenovich(1), D. Müller(1), J. Ascher(4), J. Kennedy(1)
1. Neurogenetics Section, Neuroscience Department, Centre for
Addiction and Mental Health 2. GlaxoSmithKline 3.
GlaxoSmithKline 4. GlaxoSmithKline
*arun_tiwari@camh.net
Introduction: There is considerable variability in the rate of
response and remission following treatment with antidepressant drugs
or placebo in patients. Bupropion, a commonly prescribed
antidepressant, is a dual norepinephrine and dopamine transporter
inhibitor.
Methodology: A total of 532 tagging single nucleotide
polymorphisms (SNPs) in 34 candidate genes (monoaminergic
pathways and Hypothalamic-pituitary-adrenal axis) were investigated
for association with remission and response in patients with major
depressive disorder (MDD). These patients were from four GSK
funded clinical trials in the USA in which they were treated with
either bupropion (n=319) or placebo (n=257). Analyses were
performed using conditional logistic regression. Gene-wide
corrections for multiple testing were carried out.
Results: Significant association was observed for remission
following treatment with bupropion with a SNP within the serotonin
receptor 2A gene (HTR2A, rs2770296, p corrected=0.02) and marginal
evidence for association within the angiotensin converting enzyme
gene (ACE, rs8075924, pcorrected=0.054). Response to bupropion
treatment was also significantly associated with a SNP in the
dopamine transporter gene (SLC6A3; rs6347, pcorrected=0.013) and
marginally associated with another variant within the vesicular
monoamine transporter 2 gene (SLC18A2; rs363225, pcorrected=0.059).
Among the patients that received placebo, marginal association for
remission was observed between a SNP in HTR2A (rs2296972,
pcorrected=0.055) as well as in the serotonin transporter (SLC6A4,
rs4251417, pcorrected=0.050). Placebo response was associated with
SNPs in the glucocorticoid receptor gene (NR3C1; rs1048261,
pcorrected=0.040) and monoamine oxidase A gene (MAOA; rs6609257,
pcorrected=0.046).
Conclusions: These results suggest an important role for HTR2A in
remission to both bupropion and placebo treatments. In accordance
with bupropion pharmacology, response may be associated with
genetic variation in dopamine and vesicular monoamine transporters.
Placebo response was associated with polymorphisms inNR3C1 and
MAOA.

PP258 PHENOTYPIC DEFINITION OF RESPONSE TO
LITHIUM TREATMENT IN THE CONLIGEN CONSORTIUM
M. Manchia*(1), M. Bauer(2), F. McMahon(3), T. Schulze(4), M.
Alda(1)
1. Department of Psychiatry, Dalhousie University 2. Department of
Psychiatry and Psychotherapy, Universitätsklinikum Carl Gustav
Carus, Technische Universität 3. Human Genetics Branch, Intramural
Research Program, National Institute of Mental Health, NIH, US
DHHS 4. Department of Psychiatry and Psychotherapy, University
Medical Center, Georg-August-Universität 5. Consortium on Lithium
Genetics (ConLiGen)
*mirko.manchia@dal.ca
Introduction: Bipolar disorder (BD) is a psychiatric illness with a
complex pattern of genetic susceptibility. Innovative approaches such
as genome wide association studies (GWAS) in BD have identified
mostly variants with small effect on disease risk. It is possible that
individually rare variants with relatively larger effect than common
variants may account for a large fraction of the genetic susceptibility.
The lack of conclusive genetic findings might be also related to the
phenotypic heterogeneity presented by BD. In this context, studying
more homogenous subgroups of patients, such as responders to
lithium treatment, might represent an effective strategy for
identifying genetic risk variants of the illness as well as determinants
of treatment response. The Consortium on Lithium Genetics
(ConLiGen) has been created as an international multi-centre
collaboration investigating the genetic basis of response to lithium
treatment. Currently, ConLiGen is undertaking a GWAS on a sample
of ~1,500 BD patients characterized for lithium response. In this
context, it is important to assess the key phenotypic measures and the
response to long-term lithium treatment reliability across the
participating centres.
Methodology: We measured the inter-rater reliability of the response
definition based on a 0-10 scale published and validated previously
(Grof et al. 2002, Garnham et al. 2007). Fifty-eight investigators from
20 participating sites rated a set of 12 standardized case vignettes. We
analyzed the concordance of ratings by means of Kappa (κ) and intraclass
correlation coefficient (ICC). In addition, we performed mixture
analysis of the empirical distribution of the total scale score available
for 1,336 patients using minimum message length (MML) and
frequentist Gaussian modeling. For the latter analysis we chose the
best fitting model according to the lowest values of Akaike
Information Criterion (AIC) and Bayesian Information Criterion
(BIC).
Results: Kappa scores and ICC showed a substantial level of
agreement across sites (κ = 0.68, z = 96.1; single measure ICC =
0.74). Frequentist mixture modelling of score distribution suggested
the presence of a best fitting model of three normal curves (2
component: AIC = 6,744.6, BIC = 6,756.4; 3 components: AIC
6,600.5, BIC = 6,631.7; 4 components: AIC = 6,604.5; BIC =
6,646.1) with the following parameters: non responders (mean =
0.76, SD = 1.14, proportion = 0.38), partial responders (mean = 4.6,
SD = 1.14, proportion = 0.29) and full responders (mean = 8.3, SD =
1.14, proportion = 0.33). The three component model was confirmed
by MML analysis. Both models suggested the cut-off for full
response at ≥7.
Conclusions: These findings indicate a substantial inter-rater
reliability of assessments of the response to lithium and provide
analytical support for the definition of phenotypic definition of
lithium response. The results of the inter-rater reliability analysis of
additional 16 standardized vignettes, currently rated by ConLiGen
investigators, will be presented at the conference.
201
PP259 GENETIC ASSOCIATION STUDY BETWEEN
PROOPIOMELANOCORTIN AND MELANOCORTIN-4
RECEPTOR GENE POLYMORPHISMS WITH
ANTIPSYCHOTIC INDUCED WEIGHT GAIN
N. Chowdhury*(1), A. Tiwari(1), R. Souza(4), C. Zai(1), S.
Shaikh(1), S. Chen(1), F. Liu(1), J. Lieberman(2), H. Meltzer(3), D.
Müller(1), J. Kennedy(1)
1. The Centre for Addiction and Mental Health 2. Department of
Psychiatry Columbia University and the New York State Psychiatric
Institute 3. Psychiatric Hospital at Vanderbilt University 4. Health
Sciences Graduate Program, Universidade do Extremo Sul
Catarinense
*nabilah.chowdhury@utoronto.ca
Introduction: Antipsychotic induced weight gain (AIWG) may
result in the metabolic
syndrome in schizophrenia patients. The leptin-melanocortin pathway
is important in food intake regulation and energy homeostasis. A
recent genome wide associationstudy of (AIWG) found the highest
main peak in the region of the melanocortin 4 receptor (MC4R) gene,
at the downstream marker rs489693. The precursor polypeptide
proopiomelanocortin (POMC) is cleaved to produce α-melanocyte
stimulating hormone, which stimulates MC4R to regulate food intake
and energy expenditure in the hypothalamus. Thus, we investigated
the potential role of MC4R and POMC variants with antipsychotic
induced weight gain
Methodology: Four MC4R SNPs (rs2229616, rs17782313,
rs11872992, rs8087522) and two POMC SNPs were genotyped in
237 patients who underwent treatment for chronic schizophrenia and
were evaluated for AIWG for up to 14 weeks. We compared weight
change (%) across genotypic groups using analysis of variance and
covariance for all SNPs (r2 ≥ 0.8).Variants were genotyped using
ABI TaqMan assays. In the case of a positive association, we
investigated in silico and in vitro for functional relevance of the SNP.
Results: The rs2229616 SNP was monomorphic in our population
and thus excluded from analyses. No significant genotypic or allelic
associations were found between the MC4R rs11872992,
rs17782313 or rs8087522 polymorphisms or the POMC rs1042571
and rs6713532 polymorphisms and weight gain (p > 0.05). However,
a subsequent analysis showed that patients of European ancestry who
were carriers of the MC4R rs8087522 A-allele (AG+AA) on
clozapine gained significantly more weight than non-carriers
(p=0.027). Electrophoretic mobility shift assay suggested that the
presence of the A-allele appears to create a transcription factorbinding
site.
Conclusions: In this study, we observed that the rs8087522 SNP of
the MC4R gene may be associated with AIWG in schizophrenia
patients of European origin. This SNP is present in the promoter,
alters transcription factor binding and therefore may affect MC4R
expression. This observation warrants replication in an independent
sample.

PP260 ASSOCIATION STUDY OF FUNCTIONAL
POLYMORPHISMS IN NPY GENE WITH ANTIPSYCHOTIC-
INDUCED BODY WEIGHT GAIN
E. Brandl*(1), A. Tiwari(1), O. Likhodi(1), H. Meltzer(2), J.
Kennedy(1), D. Müller(1)
1. Neurogenetics Section, Centre for Addiction and Mental Health 2.
2Psychiatric Hospital, Vanderbilt University
*eva_brandl@camh.net
Introduction: Significant body weight gain (BWG) is a serious sideeffect
of a number of antipsychotic drugs. Previous studies have
demonstrated an influence of clozapine, but not haloperidol on
Neuropeptide Y (NPY) expression in the brain. Since NPY is a potent
orexigenic peptide stimulating food intake and genetic variation of
the gene has been shown to influence development of obesity, we
investigated the impact of NPY polymorphisms on antipsychoticinduced
BWG.
Methodology: We analyzed four polymorphisms in the NPY gene
(rs16147, rs16475, rs5573 and rs5574) in schizophrenia subjects
(n=80), undergoing first exposure to clozapine for 6 weeks.
Association was tested using analysis of covariance with change (%)
from baseline weight as the dependent variable and baseline body
weight as covariate.
Results: A significant association of rs16147 genotype with weight
change was observed (p=.002) in patients of European ancestry.
Carriers of the C-allele gained significantly more weight compared to
individuals with TT-genotype (TC+CC vs. TT; 5.61±5.4 vs.
0.32±4.8). Similarly, two other polymorphisms (rs5573 and rs5574)
were also significantly associated with weight change (p=.009 and
p=.022). The three associated polymorphisms are in high linkage
disequilibrium with each other. There was no association of rs16475
(p=.654).
Conclusions: Our observation of association of NPY polymorphisms
gives further evidence for a genetic influence on antipsychoticinduced
BWG. The polymorphism rs16147, present in the promoter
region, has been previously described to affect NPY expression both
in vivo and in vitro. However, these results warrant replication in
independent and larger samples.
202
PP261 GENETIC VARIATION IN BDNF IS ASSOCIATED
WITH ANTIPSYCHOTIC TREATMENT RESISTANCE IN
PATIENTS WITH SCHIZOPHRENIA
J. Zhang*(1), T. Lencz(1), S. Geisler(1), P. DeRosse(1), E.
Bromet(2), A. Malhotra(1)
1. Zucker Hillside Hospital 2. Brook University School of Medicine
*jzhang1@nshs.edu
Introduction: Antipsychotic drugs are the mainstay of treatment for
schizophrenia. However, a substantial proportion of patients are
poorly responsive or resistant to treatment resistant to first-line
treatments, and clozapine treatment is therefore often indicated.
Therefore, we and others have used clozapine treatment as a proxy
phenotype for antipsychotic treatment resistance in pharmacogenetic
studies that aim to identify predictors of antipsychotic treatment
resistance.
Methodology: We assessed 89 schizophrenia patients clinically
assigned to clozapine treatment versus 190 patients that were not
selected for clozapine treatment All were Caucasians. 64.5% were
males. To minimize multiple comparisons, we tested a set of 74
candidate genes that were associated with all-cause discontinuation at
the p

AUTHOR INDEX
203

A
A.S. Joshi, A., 160
Aalto, M., 155
Abdellaoui, A., 29
Abdul Rahman, O., 195
Aberg, K., 23, 44, 53, 170
Abramson, L., 119
Adachi, Y., 68
Adkins, A., 62, 165
Adkins, D., 199
Agartz, I., 85, 120, 171
Aggen, S., 88
Agrawal, A., 56, 150
Aguilar, A., 125
Ahmadkhaniha, H., 109
Ahn , Y., 133, 177
Aitchinson, K., 186
Ait-­‐Daoud, N., 161
Ajit, D., 152
Akahane, A., 188
Akiskal, H., 127
Akterin, S., 62, 97
Akula, N., 40, 55, 59, 64
Alasaari, J., 110
Alda, M., 3, 50, 172, 201
Aleksic, B., 68
Aleksic, B., 70, 75
Aleman, A., 115
Alexander, M., 52
Alho, H., 155
Ali, I., 178
Aliev, F., 62, 148, 181
Al-­‐Janabi, T., 42
Allencherry, P., 170
Almasy, L., 46, 47, 126, 150
Alonso, P., 80
Althoff, R., 29
Amdur, R., 23
Ameis, S., 48
Amelang, M., 122
Amin, N., 87
Anbazhagan, P., 42
Andersen, J., 175
Andreasen, N., 101
Andreassen, O., 16, 85, 120,
171
Andreou, D., 171
Anjanappa , R., 179
Anney, R., 92
Antal, P., 123
Antonijevic, I., 197
Appel, K., 169
Apud, J., 48
Aqil, A., 83
Arad, M., 31
Ardau, R., 50
Arenovich, T., 200
Arias-­‐Vásquez, A., 83, 87
Arkhipov, A., 183
Arnold, P., 139, 140
Arnold, S., 34
Arranz, M., 51, 199
Arun, M., 107
Ascher, J., 200
Asherson, P., 74, 113, 193
Ashley-­‐Koch, A., 167
Aslanidou, P., 63
Athanasiu, L., 85, 120
Aukes, M., 117, 125, 176
Avrabos, C., 5
Avramopoulos, D., 104, 122
Axelsen, M., 101
Ayalew, M., 66
Ayub, M., 100
Ayyappan, A., 124, 183
Azzouz, F., 5
B
Bacanu, S., 22
Backlund, L., 130
Badner, J., 21, 22, 90
Bagepally, B., 142
Bailey, M., 77
Bajo, E., 198
Baker, M., 109
Bakker, S., 125, 130
Balachandar, V., 107
Balaraman, Y., 66
Balhara, Y., 154
Bamne, M., 64
Banaschewski, T., 74, 113
Banerjee, M., 170
Banno, M., 68
Barbacioru, C., 45
Barnes, C., 190
Barr, C., 45, 109
Barrett, J., 25
Barta, C., 166
Bartels, M., 29
Bassett, A., 128
Bauer, M., 201
Bayés, À., 16
Becker, T., 87
Belmonte-­‐de-­‐Abreu, P., 189
Benedek, D., 185
Benegal, V., 160
Bennett, V., 30
Bergen, S., 62, 118
Berlim, M., 8
Bermudez Ocaña, D., 182,
186
Berrettini, W., 5
Berry-­‐Scott, E., 31
Bertelsen, S., 150
Bettinger, J., 62
Bialosuknia, S., 69
Bickeböller, H., 116
Bidwell, L., 167
Biernacka, J., 49
Bierut, L., 17, 19, 79, 126,
147, 150
Bigelli, M., 198
Binder, E., 9, 35, 36, 39, 49,
52, 123, 186
Birkenaes, A., 85
Bishop, J., 141
Bitsios, P., 32, 114
204
Björk, K., 45
Blackwood, D., 73, 100
Blaine, S., 159
Blake, D., 20, 42
Blakemore, A., 199
Blangero, J., 46, 47, 103
Blaya, C., 131
Bloom, R., 89, 91
Blum, K., 196
Bochdanovits, Z., 115
Bognár, Z., 136
Bogue, M., 199
Bohlen, K., 200
Bohn, B., 87
Boks, M., 117, 125, 176, 182
Bollen, J., 197
Bonde, J., 175
Bonetto, C., 157
Boomsma, D., 29, 87
Boos, H., 130
Borglum, A., 176, 180
Børglum, A., 78, 95, 169,
175
Bortoluzzi, A., 131
Bosa, V., 131
Böttcher, Y., 15
Bowers, S., 62
Braaten, E., 129
Bradley, B., 36, 200
Bramon, E., 51, 112
Brand, J., 135
Brandl, E., 40, 202
Bravo, H., 55
Bray, N., 21
Breakspear, M., 4
Breen, G., 96, 191, 193
Breetvelt, E., 125, 128
Brentani, H., 189
Breuer , R., 85
Breuer, R., 72, 180
Brij , K., 152
Britto Junior, A., 178
Brockmöller, J., 116
Bromet, E., 202
Broms, ., 153
Brown, A., 85, 120
Brunner, H., 175
Brusniak, W., 120
Bubb, V., 46, 164
Bucholz, K., 56, 126
Buckner, R., 140
Budde, J., 150
Budde, M., 116
Bui, E., 107
Buitelaar, J., 52, 74
Buizer-­‐Voskamp, J., 176
Bukszár, J., 23, 44, 53, 170
Bulik, C., 98
Burdick, K., 15, 135
Burdick, M., 33, 83
Burke, A., 37
Burrell, H., 164
Buttenschøn, H., 175
Buxbaum, J., 26
Byerley, W., 90
C
Caballero, A., 139
Cahn, W., 130
Cai, X., 5, 31
Cain, G., 152
Cairns, M., 92
Calati, R., 197
Callicott, J., 33, 48, 83, 142
Camarena Medellin, B., 182,
186
Camarena, B., 125, 139
Campbell, J., 186
Campos, L., 139
Cannon, T., 89
Cantor, R., 117
Carless, M., 46, 47, 103
Carlson, G., 34
Carr, G., 33
Carrard, A., 68
Carraro, D., 189
Carter, C., 121
Carvalho, F., 158
Casey, B., 36
Casey, D., 163
Castelao, E., 88
Castellani, C., 90
Castro R, R., 104
Chai, Y., 49
Chakrabortty, A., 57
Chakravarti, A., 13, 54
Chambert, K., 15, 16, 55, 56,
62, 80, 101, 129
Chan, W., 72
Chang, S., 172
Chapman, J., 60
Chatterjee, N., 59
Chen, C., 21, 22, 163, 193
Chen, D., 59
Chen, G., 89, 148
Chen, H., 145, 192
Chen, J., 22, 33, 83, 146
Chen, L., 17, 79
Chen, P., 122
Chen, Q., 48, 142
Chen, S., 71, 201
Chen, X., 22, 24, 146
Chen, Y., 131
Cheng, A., 59
Cheng, L., 21, 22
Cheng, M., 163
Chiano, M., 200
Chiesa, A., 197
Chillotti, C., 50
Chitkara, N., 44
Cho, M., 63
Choi, K., 55, 185
Chow, E., 128
Chow, T., 189
Chowdari, K., 178
Chowdhury, N., 40, 201
Christensen, J., 176
Christoforou, A., 93
Chun, J., 174

Cichon, S., 15, 16, 59, 72, 78,
85, 87, 91, 93, 180
Clark, A., 23
Claus, E., 159
Cohen, M., 141
Cohen, O., 69
Cohen-­‐Woods, S., 96, 191
Coleman, M., 112
Collier, D., 16, 98, 134, 157
Collins, A., 89, 91, 99
Colombo, E., 145
Colombo, R., 145
Congiu, D., 50
Conrad, D., 190
Cooper, P., 134
Coppola, G., 194
Corley, R., 156
Cormican, P., 92
Cornelisse, L., 26
Corry, J., 4
Corvin, A., 15, 20, 92, 136
Coryell, W., 31
Costa, M., 50
Cotsapas, C., 28
Courchesne, E., 121
Cox, N., 22
Craddock, N., 47, 58, 59, 89,
138, 159, 190
Craig, I., 96, 186, 191
Crawley, J., 83
Crespo , J., 132
Creswell, C., 134
Crisafulli, C., 187, 197
Crisponi, L., 72
Cristofalo, D., 157
Crow, T., 111, 195
Crowley, J., 76, 199
Cullis, J., 172
Curran, J., 46, 47
Currier, D., 37
Curtis, D., 57
Czibere, L., 5
Czisch, M., 9
D
D'Aiuto, L., 64
Dai, N., 81
Daly, M., 26, 28
Dao, D., 31
Darvasi, A., 96
Dauwan, M., 117
Davies, G., 93
Davies, G., 29, 51, 196, 200
de Geus, E., 29, 87
de Jong, S., 182
de Leon, J., 199
De Luca, V., 102, 111, 154,
158
De Ronchi, D., 145, 187, 197
De Santi, K., 157
De Souza Silva, M., 43
Deary, I., 93
Degenhardt, F., 72, 85, 87,
180
Degenhardt, L., 56
Del Zompo, M., 50
Deldin, P., 174
Demenescu, L., 115
Demetrovics, Z., 123, 166
Demirakca, T., 120
DeModena, A., 39
Demontis, D., 78, 95, 169,
176, 180
Dempster, E., 45
Derks, E., 58, 73
DeRoode, D., 149
DeRosse, P., 202
Desrivières, S., 43, 158, 184
Desta, Z., 49
Detera-­‐Wadleigh, S., 55, 64,
185
Devlin, B., 26
Di Florio, A., 159
Di Maio, R., 64
Di Nicola, M., 145
Dick, D., 61, 62, 146, 148,
165
Dickinson, D., 83
Didriksen, M., 95, 169, 180
Diener, C., 120
Dierssen, M., 184
Dijkstra, T., 26
Dixson, L., 9
Djurovic, S., 85, 120
do Prado, C., 114
Dobson, R., 21, 61, 194
Dolan, C., 29
Domenici, E., 7
Donner, J., 76
Donohoe, G., 20, 92, 136
Doty, N., 129
Doucette, S., 3
Doyle, A., 129
Drago, A., 162, 187
Drain, C., 3
Drews, M., 49
Drigalenko, E., 53, 79
Drury, S., 112
Duan, J., 53, 79, 94
Duffy, A., 3
Duggirala, R., 46, 47
Duong, L., 129
Dwyer, S., 77, 84, 136
Dyer, T., 46, 47, 103
E
Easter, P., 140
Easton, A., 43
Ebstein, R., 74
Edenberg, H., 126, 148, 150
Eder, M., 5
Ehlers, C., 143
Ehli, E., 29, 51, 196, 200
Ehringer, M., 147
Eisinger, A., 166
Eissa, A., 178
Elassy, M., 178
El-­‐Bahaei, W., 178
Elek, Z., 134, 136
Eley, T., 134
205
Elfving, B., 175
el-­‐Guebaly, N., 163
Elhaik, E., 54
Ellonen, P., 6
Elsayed, H., 178
Elves, R., 98
Elvevaag, B., 83
Emese, K., 191
Ende, G., 120
Engberg, G., 130
Enoch, M., 71
Erhardt, A., 6
Erhardt, S., 130
Erickson, J., 63
Erickson, L., 83
Eriksson, J., 155, 190
Erk, S., 32
Escaramís , G., 132
Espeseth, T., 93
Essex, M., 126
Estivill, 132
Estivill, X., 80, 184
Eszter, K., 191
Etemad, B., 50
Eubanks, J., 45
Evgrafov, O., 23
F
Fabbri, C., 156
Fagerness, J., 140
Fahey, C., 92
Fajardo, L., 178
Falkai, P., 116
Faludi, G., 134, 195
Fanous, A., 23, 24
Fanous, S., 164
Faraone, S., 65, 69, 74, 97,
113
Farkas, J., 166
Farmer, A., 59, 96, 134, 191
Fasmer, O., 127
Fathi, W., 178
Faundez, V., 33
Feiler, H., 143
Feng, Y., 45
Fernandes, A., 43
Fernandes, C., 43, 93, 187
Fernandez, E., 16
Fernández, G., 175
Ficks, C., 179
Fisher, C., 3
Flockhart, D., 49
Flor, H., 120, 137
Flores, G., 139
Flores, J., 188
Foldager, L., 95, 169, 175
Forray, C., 197
Forty, L., 47, 59, 89, 138
Fox, N., 112
Fox, P., 47
Frank, J., 72, 122, 180
Franke, B., 52, 87, 97, 175
Frankland, A., 4
Franziska Degenhardt, M.,
16
Freda, J., 53, 79, 94
Freeman, N., 40
Freudenberg, J., 105
Freudenberg-­‐Hua, Y., 105
Freyberger, H., 169
Frias-­‐Ramón, T., 182, 186
Friderici, K., 93
Friedman, N., 156
Frisén, L., 130, 135
Fromer, M., 55, 101
Fuemmeler, B., 167
Fukumoto, M., 117, 118
Furlong, S., 92
G
Galfalvy, H., 37
Gallagher, L., 92
Gallego, J., 44
Galloway, B., 172
Gálvez, V., 132
Gamazon, E., 22
Gandal, M., 34
Garrett, M., 167
Gaudi, S., 88
Geels, L., 29
Geisler, S., 202
Gejman, P., 53, 79, 94
Genis, A., 182, 186, 188
Genome Study, B., 127
Gentile, J., 44
Georgieva, L., 80
Gergely, K., 191
Gerrish, A., 60
Gershon, E., 5, 15, 21, 22
Gerstner, T., 87
Geschwind, D., 194
Geyer, M., 66
Ghadami, M., 172
Ghadiri, M., 109
Ghosh, S., 57, 179
Giakoumaki, S., 32, 114
Gibbs, R., 26, 76
Giegling, I., 136
Giese, K., 43
Gilder, D., 143
Gill, M., 20, 74, 92, 113
Gillies, S., 164
Gizer, I., 143
Glahn, D., 46, 47, 103
Glatt, C., 36
Glatt, S., 69, 121
Glennon, J., 52
Glessner, J., 70
Glowinski, A., 5
Goate, A., 126, 148, 150
Goes, F., 54, 95
Goldani, M., 131
Goldart, E., 164
Goldberg, T., 135
Goldman, D., 13, 37, 71
Goldsmith, H., 126
Goldstein, J., 118
Gomaa, Z., 178
Gomez, L., 45
Gonzalez, L., 139

Gopin, C., 135
Gordano, J., 196
Gordon, M., 44
Gordon-­‐Smith, K., 47, 59,
89, 138
Göring, H., 47, 53, 79
Gould, T., 31
Grabe, H., 169
Grant, S., 11, 16
Gratacòs, M., 80, 132, 184
Greco, D., 6
Green, E., 47, 59, 89
Green, M., 4
Greenwood, T., 127
Gregersen, P., 105
Grennan, K., 22
Griebel, M., 87
Grigoriou, E., 63
Groen-­‐Blokhuis, M., 29
Grof, P., 3
Grove, J., 78, 95, 169, 176,
180
Grozeva, D., 15, 47, 59, 80,
89, 190
Gruber, O., 116
Grynderup, M., 175
Guennel, T., 22
Guha, S., 96
Guindalini, C., 165
Guipponi, M., 7
Gupta, A., 25
Gupta, J., 66
Gur, R., 34
Gurling, H., 176
Gustafsson, O., 120
Gutiérrez-­‐Zotes , A., 132
H
Haavik, J., 127
Hack, L., 155, 165
Haddad, S., 172
Haddley, K., 46, 164
Hadzi-­‐Pavlovic, D., 4
Haenisch, B., 87
Hakonarson, H., 70
Halagur BhogeGowda , K.,
179
Hall, H., 171
Hall, M., 112
Hallett, V., 174
Hamilton, G., 77
Hamilton, S., 166
Hamshere, M., 47, 74, 89
Hänisch, B., 72
Hanna, G., 139, 140
Hansell, N., 124
Hansen, A., 175
Hansen, T., 129
Happé, F., 174
Häppölä, A., 153
Hargreaves, A., 20
Härmä, M., 110
Harold, D., 60
Harris, R., 151
Hartz, S., 19, 147
Hashimoto, R., 70, 117, 118
Hassan, A., 111
Hata, T., 188
Hatton, D., 99
Hattori, E., 81
Haughey, H., 159, 160
Hauser, J., 7
Hawi, Z., 74
He, D., 53, 79, 94
He, G., 71, 198
He, L., 71, 198
Headings, V., 152
Heath, A., 56
Heath, B., 64
Hebbring, S., 49
Hedemand, A., 78
Heikkilä, K., 153
Henders, A., 56
Hennekam, E., 176
Herms, S., 85, 87
Hernández, S., 125, 139
Heskes, T., 26
Hesselbrock, V., 150
Hettema, J., 88
Hewitt, J., 156
Hill, E., 129
Hill, M., 21
Hilliard, C., 76
Hinrichs, A., 150
Hipolito, M., 108, 194
Hiroshi, U., 70
Hodge, S., 166
Hodges, A., 194
Hodgkinson, C., 37
Hoeben, W., 125
Hoft, N., 147
Höhn, D., 9
Hollegaard, M., 78, 95, 169,
180
Hollingworth, P., 60
Holmans, P., 16, 58, 73, 74,
175
Holmboe, K., 174
Holmes, A., 7, 140
Holsboer, F., 9, 49, 52, 85
Hoogendijk, W., 115
Hope, B., 164
Horrocks, J., 3
Hosang, G., 191
Hottenga, J., 29, 87
Hougaard, D., 78, 95, 169,
180
Hovatta, I., 6, 76, 190
Hu, X., 7
Hu, Y., 29, 51, 196, 200
Huang, K., 110
Huang, Y., 37, 193
Hudson, J., 134
Hudziak, J., 29, 51
Huganir, R., 104
Huizenga, P., 29, 196
Hukic, D., 135
Hulse, G., 82
Hulshoff Pol, H., 130
Hultman, C., 44, 55, 56, 62,
89, 97, 101
206
Humberto, N., 182
Hunter, R., 77
Hurles, M., 190
Hutchinson, K., 159
Hyde, J., 119
Icay, K., 6
Iidaka, T., 68
Ikeda, M., 15, 68, 70, 75, 80
Ilsley, K., 31
Inada, T., 68, 70, 75
Ingason, A., 16, 129
Inkster, B., 9
Insel, T., 12
Investigators, R., 96, 191
Iossifov, I., 95
Ira, E., 157
Ising, M., 49
Ismail, T., 124, 183
Ivanov, D., 15, 16, 80, 171
Iwase, M., 117, 118
Iwata, N., 68, 70, 75, 118
Iwayama, Y., 81, 124
Jacobi, J., 53, 79, 94
Jacobsen, I., 176
Jain, S., 142
Jain, S., 42, 160, 179
Jakobsen, K., 129
Jamain, S., 59
Janiri, L., 145
Janson, E., 117, 182
Janus, K., 151
Jeffries, A., 21
Jeffries, C., 103
Jenkins, G., 49
Jentsch, J., 34
Jhuang, H., 31
Ji, Y., 49
Jia, P., 24
Jiang, T., 70
Jiang, X., 59, 185
Jimenez Santos, A., 182
Jiménez Z, C., 104
Johansson, S., 127
Johnson, B., 160, 161
Johnson, L., 185
Johnson, M., 47
Jones, I., 47, 59, 89, 100,
138
Jones, L., 42, 47, 59, 73, 89,
138
Jönsson, E., 120, 171
Joo, E., 133
Jovanovic, T., 36
Juárez Rojop, I., 186
Juárez Rojp, I., 182
Juhila, J., 6
I
J
K
Kærgaard, A., 175
Kærlev, L., 175
Kähler, A., 89, 97, 99, 120
Kahn, R., 58, 117, 125, 130,
176, 182
Kaibuchi, K., 75
Kajantie, E., 190
Kallahalli Jayramu , S., 179
Kalu, N., 152
Kamali, M., 5, 174
Kamatani, N., 49
Kamijima, K., 118
Kamino, K., 117
Kam-­‐Thong, T., 9
Kan, K., 29
Kananen, L., 76, 190
Kanazawa, T., 69, 82
Kanba, S., 81
Kaneko, T., 69
Kang, S., 126, 150
Kapitany-­‐Foveny, M., 166
Kaplan, A., 113
Kapoor, M., 150
Kaprio, J., 146, 153
Karagiannidis, J., 63
Karayiorgou, M., 15
Karchin, R., 54, 95
Karege, F., 68
Kasper, S., 197
Kassem, L., 3, 59, 107
Kato, M., 81
Kato, T., 81
Katsanis, N., 12
Kawashige, S., 69
Kay, V., 199
Kazuba, D., 3
Kazui, H., 117, 118
Keddy, P., 50
Kelsoe, J., 15, 39, 127
Kember, R., 187
Kendler, K., 22, 24, 62, 98,
148, 155, 165
Kennedy, J., 40, 48, 102,
111, 113, 139, 140, 154,
158, 163, 200, 201, 202
Kenny, E., 92
Kenny, P., 17
Kent, J., 47
Kent, L., 74
Kepa, A., 184
Khachane, A., 23, 44, 170
Khondoker, M., 75
Kikuchi, T., 68
Kikuyama, H., 82
Kim, S., 78, 177
Kim, Y., 76, 91, 133, 177,
199
Kimura, M., 71
Kiran, H., 160
Kircher, T., 32
Kirov, G., 15, 16, 77, 80,
171, 190
Kishore, B., 160
Kleiber, M., 151
Knight, D., 42
Knowles, J., 23, 31, 100
Kochunov, P., 47

Koefoed, P., 120
Koenen, K., 35
Koh, J., 69, 82
Kohli, M., 9, 52
Kohmura, K., 68
Koide, T., 68, 70
Kolachana, B., 48
Kollins, S., 167
Kolstad, H., 175
Komel, R., 173
Komiyama, N., 16
Kooij, S., 87
Korhonen, ., 153
Kovacsics, C., 31
Kovács-­‐Nagy, R., 134
Kovanen, L., 155
Kovas, Y., 128
Kraft, P., 19
Kramer, J., 126, 148, 150
Kramer, M., 54
Kranz, J., 47, 59, 89
Kraus, L., 123
Kreek, M., 141
Krieger, J., 165
Krishna, N., 179
Kronholm, E., 94, 177
Krug, A., 32
Kubo, M., 49
Kuczenski, R., 66
Kuehner, C., 32
Kuntsi, J., 74, 113
Kunugi, H., 118
Kuperman, S., 150
Kuryatov, A., 18
Kushima, I., 70, 75
Kusumawardhani, A., 81
Kutalik, Z., 88
Kutscher, E., 200
Kwagyan, J., 152
Kwan, J., 28
L
Laan, W., 176
Labbe, A., 8
Labonte, B., 38
Lachman, H., 65
Lage, K., 28
Lagus, M., 110
Lahti, J., 155
Lahti, M., 190
Lai, C., 163
Laite, G., 5
Laje, G., 40, 55
Landén, M., 62, 130
Landgraf, R., 5
Langley, K., 74
Laranjeira, R., 165
Largeau, ., 153
Lasalvia, A., 157
Lassen, N., 95
Lavebratt, C., 45, 130, 135
Lawrie, S., 116, 141
Lawson, W., 31, 108, 194
Le Hellard, S., 93
Le, T., 185
Leal, S., 11
Leask, S., 111
Leboyer, M., 59
Leckband, S., 39
Lee, F., 36
Lee, K., 133
Lee, P., 27, 112, 140
Lehner, T., 12
Leibenluft, E., 15
Leistner-­‐Segal, S., 131
Lemery-­‐Chalfant, K., 126
Lencz, T., 44, 54, 96, 202
Le-­‐Niculescu, H., 66
Lennartsson, A., 45
Lenroot, R., 4
Leong, L., 78
Lerch, J., 48
Lerer, B., 88
Lester, K., 134
Lett, T., 40, 48
Leussis, M., 31
Levinson, D., 31, 102
Levitan, R., 113
Levran, O., 141
Levy, D., 15, 112
Levy, F., 4
Lewis, C., 51, 96, 127, 134,
173, 191
Lewis, D., 95
Lewis, G., 7
Lewitzka, U., 3
Li, H., 185
Li, M., 28, 160, 161
Li, X., 71, 198
Liao, D., 163
Liao, H., 163
Lichtenstein, P., 56, 62, 97,
101, 173
Lieberman, J., 40, 48, 76,
201
Liebsch, K., 120
Liew, C., 121
Ligthart, L., 29
Likhodi, O., 40, 202
Lima de Souza, A., 178
Lin, D., 91
Lin, K., 51
Lin, M., 65
Lindell, S., 109
Lindstrom, J., 18
Lino, B., 4
Linotte, S., 197
Littlefield, A., 56
Liu, B., 71, 198
Liu, C., 21, 22
Liu, F., 201
Liu, H., 5
Liu, Q., 164
Liu, X., 84
Liu, Y., 53, 70, 170, 196
Lobina, M., 72
Lobo, D., 163
Lodhi, S., 149
Loerbroks, A., 122
Logan, R., 45
Loh, H., 181, 189
207
Lohoff, F., 50
Loken, E., 98
Lönnqvist, J., 76
López N, M., 104
Lopez, J., 8
Lopez, L., 121
Lopéz-­‐Rubalcava , C., 188
Losh, M., 99
Loukola, A., 146, 153
Lourdusamy, A., 61
Lovestone, S., 61, 194
Lóyzaga, C., 125
Lu, L., 149
Lucae , S., 85
Lucae, S., 9, 49, 52
Lucchesi, W., 43
Luna, A., 83
Lundervold, A., 93
Lunnon, K., 61, 194
Luo, L., 193
Luyxk, J., 125
Lyneham, H., 134
Lynskey, M., 56
Lyon, G., 70
M
Macciardi, F., 88
MacGregor, S., 73
Machado-­‐Vieira, R., 114
Maclean, A., 73, 100
Madden, P., 56
Maes, H., 146, 155
Magi, A., 166
Magnusson, P., 44, 97
Maher, B., 88
Mahmood, K., 100
Mahmoodizadeh, A., 172
Mahon, P., 31
Maier, W., 7, 85, 87
Maiti, S., 90
Majumder, S., 161
Malafosse, A., 7, 68
Malhotra, A., 15, 44, 54, 96,
135, 202
Malhotra, D., 15
Malik, M., 194
Malki, K., 186
Mamdani, F., 8
Manchia, M., 50, 172, 201
Mandelli, L., 145
Manduva , V., 179
Manduva, V., 86
Manfro, G., 131
Mann, J., 37
Mannila, H., 137
Männistö, S., 94
Manor, I., 113
Mansour, H., 178
Manz, N., 126, 150
Marangon, V., 157
Maria, S., 191
Markt, P., 5
Márquez, L., 125
Marshall, V., 152
Martin, E., 141
Martin, N., 56, 124
Martínez G, M., 104
Martinotti, G., 145
Martorell , L., 132
Maschieto, M., 189
Mash, D., 71
Massat, I., 197
Mathé, A., 45
Matsuzaki, H., 183
Mattay, V., 48, 142
Matthäus, F., 120
Mattheisen, M., 72, 78, 85,
87, 180
Matthews, P., 9
Mattingsdal, M., 85, 120
Maussion, G., 38
Mavruk, S., 95
May, C., 161
May, V., 36
Mayfield , R., 151
Mazza, M., 145
McCarley, R., 118
McCarthy, M., 39
Mccarthy, S., 15, 90
McClay JL, J., 53
McClay, J., 23, 44, 170
McClernon, F., 167
McCombie, W., 54, 90, 95
McCormack, C., 4
McCue, C., 4
McDonald, J., 184
McGuffin, P., 59, 96, 127,
173, 186, 191
McGuire, J., 185
McInnis, M., 4, 5, 174
McIntosh, A., 116, 141
McKechanie, A., 73
Mckenzie, B., 154
McLeod, H., 199
Mcmahon, F., 15, 40, 55, 59,
64, 107, 185, 201
McMahon, W., 70
McMichael, O., 62
McQuillin, A., 176
McRae, A., 73
Meaney, M., 38
Meary, A., 68
Medeiros, H., 23
Meera , P., 152
Mehta, D., 123
Meichle, S., 78
Meier, S., 72, 85, 120, 122
Meirelles, O., 72
Melas, P., 45
Melle, I., 85, 120
Mello, B., 189
Meltzer, H., 40, 48, 201, 202
Meltzer-­‐Brody, S., 100
Menchón, J., 132
Mendlewicz, J., 197
Mendoza, P., 188
Mercer, K., 36
Merwood, A., 74
Messas, G., 165
Meta-­‐Analysis Group, C., 17

Meyer-­‐Lindenberg, A., 19,
132
Meyers, J., 146
Michael, G., 136
Michael, O., 175
Mick, E., 97
Middeldorp, C., 29
Middleton, F., 65, 69
Mikkelsen, S., 175
Miliar G, A., 104
Mill, J., 158, 187
Millard, S., 78
Miller, G., 148
Miller, M., 196
Mills, N., 124
Mir, A., 100
Miranda, A., 74, 113
Missaglia, S., 145
Mitchell, P., 4, 5
Miyake, A., 156
Monnier, P., 45
Montgomery, G., 56
Moore, B., 70
Moore, M., 126
Moran, J., 15, 16, 47, 55, 56,
59, 62, 80, 89, 101, 129
Morell, C., 44
Moreno, R., 114
Morgan, M., 76
Mori, N., 124, 183
Morihara, T., 117
Morris, B., 77
Morris, D., 20, 92
Morris, N., 82
Mors, O., 7, 78, 95, 120, 169,
175, 176, 180
Mortensen, P., 78, 95, 169,
180
Moses, E., 47
Moskvina, V., 58
Mostafavi Abdolmalek, H.,
109
Mostafavi, S., 109
Mould, G., 113
Moumita, M., 152
Moy, W., 53, 79, 94
Mozhui, K., 149
Mrazek, D., 49
Muck Seler, D., 173
Mueller, K., 193
Mueller-­‐Myhsok, B., 49
Muglia, P., 59, 191
Mühleisen , T., 85
Mühleisen, T., 72, 87, 180
Mukherjee, O., 142
Mulas, A., 72
Mulas, F., 113
Muller, C., 43
Müller, D., 40, 48, 200, 201,
202
Müller-­‐Myhsok, B., 9, 52, 85
Mulsant, B., 48
Multani, P., 50
Munro, J., 199
Murdoch, J., 25
Murphy, E., 3
Murray, J., 193
Murray, R., 51, 112
Murtha, M., 25
Murthy A, R., 86
Murthy, P., 160
Mushiroda, T., 49
Myers, A., 36
Myers, J., 155
Myers, P., 46, 164
N
Naeem, F., 100
Naik, R., 5
Nair, C., 170
Nakamura, J., 145, 192
Nakamura, K., 124, 183
Nakamura, M., 81
Nakamura, Y., 49, 70
Nanko, S., 188
Narasimhan, S., 50
Neale, B., 26, 28, 60, 129
Neary, J., 46, 103
Nedic, G., 173
Nees, F., 137
Negrão, A., 165
Negri, G., 145
Nelson, C., 112
Nelson, E., 56
Nelson, K., 29, 196
Németh, N., 136, 166
Nemoda, Z., 123, 195
Nerella, S., 23, 44
Newport, J., 123
Nicodemus, K., 83
Nicolae, D., 22
Nicolini, H., 125, 186, 188
Niculescu, A., 66, 108
Nieratschker, V., 120, 122,
137
Nigg, J., 93
Nikolac, M., 173
Nikolas, M., 93
Nimgaonkar, V., 64, 178
Nishiguchi, M., 82
Nivard, M., 29
Nohesara, S., 109
Nordentoft, M., 78
Nossova, N., 121
Nöthen, M., 72, 85, 87, 91,
180
Numans, M., 125
Nummy, K., 93
Nurnberger , J., 5, 150
Nurnberger Jr, J., 108, 148,
194
Nwulia, E., 108, 147, 152,
194
Nyman, E., 146
O
O'Donnell, L., 174
O'Donovan, M., 7, 15, 16, 42,
47, 58, 59, 73, 74, 77, 80,
84, 86, 89, 136, 171, 190
208
O'Dushlaine, C., 27, 56, 62,
129
O'Neill, F., 98
O'Reilly, R., 90
Oades, R., 74, 113
Oedegaard, K., 127
Ohi, K., 70, 117, 118
Ohmori, O., 145, 192
Okochi, T., 118
Olason, P., 15
Olgiati, P., 198
Ollila, H., 94, 138, 177
Olsson, S., 130
Olvera, R., 47
Ophoff, R., 16, 117, 125,
130, 176, 182
Opmeer, E., 115
Oquendo, M., 37
Ørntoft, T., 95, 169, 180
Ösby, U., 62, 130, 135
Oscar-­‐Berman, M., 196
Osimo, E., 88
Ossowski, S., 80
Ostrosky, P., 188
Otowa, T., 88
Owen, M., 15, 16, 42, 47, 58,
59, 60, 74, 77, 80, 84, 86,
89, 136, 171, 190
Ozaki, N., 68, 70, 75, 118
P
Pae, C., 197
Palha, J., 189
Pallesen, J., 78, 95, 176
Palotie, A., 16, 25, 155
Papaleo, F., 83
Papasotiriou, S., 63
Papeleo, F., 33
Park, J., 59
Parla, J., 54, 95
Partonen, T., 94, 138, 155
Paschou, P., 63
Pasparakis, M., 32
Patel, S., 66
Pato, C., 23
Pato, M., 23
Patterson, D., 165
Pattwell, S., 36
Pauline, M., 141
Pauls, D., 52
Paunio T, T., 153
Paunio, T., 94, 110, 137,
138, 177
Payo-­‐Cano, J., 186
Pedersen, C., 78, 95, 180
Pedrosa, E., 65
Pendleton, N., 93
Peng, Z., 22
Penninx, B., 30, 87, 100, 115
Pereira, A., 165
Pereira, C., 189
Pergadia, M., 56, 153
Perkins, D., 103
Perlis, R., 38, 79
Perola, M., 94, 138
Perrine, K., 196
Perroud, N., 7, 68
Perry, J., 191
Peterson, R., 146
Petryshen, T., 31, 118
Pibiri, F., 21, 22
Pickard, B., 73
Pickens, C., 164
Pierce, K., 121
Piras, C., 50
Piras, M., 72
Pirkola, S., 76
Pirooznia, M., 54, 95, 104
Pitkäniemi, J., 153
Pivac, N., 173
Piven, J., 99
Platt, D., 148
Plomin, R., 128, 174
Pocklington, A., 16, 27, 74
Poelmans, G., 52
Poggio, T., 31
Pohlack, S., 137
Ponomarev, I., 151
Pool García, S., 182
Popoli, M., 8
Porcelli, S., 156
Porjesz, B., 126, 150
Potash, J., 15, 31, 54, 95,
104
Potkin, S., 40, 48
Poulsen, P., 175
Powell, J., 51, 61
Powell, T., 187
Power, R., 127, 173
Prabhat, C., 152
Prabhu, S., 42, 142
Pradip, P., 152
Pratima, M., 152
Pratt, A., 199
Pratt, J., 77
Pregelj, P., 173
Preisig, M., 88
Prescott, C., 62, 165
Price, J., 21
Price, T., 74, 113
Priebe, L., 72, 85
Proitsi, P., 61, 194
Propping, P., 87
Puga, R., 189
Pulver, A., 122
Purcell, S., 15, 16, 27, 47,
55, 56, 59, 62, 73, 76, 80,
89, 97, 101, 118, 129,
140
Purushottam, M., 42, 142,
160, 179
Puttonen, S., 110
Q
Qi, H., 45
Qin, W., 81
Quackenbush, C., 199
Quinn, J., 46, 164

R
Radant, A., 78
Räikkönen, K., 155, 190
Raimondi, G., 64
Rajji, T., 48
Rajkumar, A., 176
Ramanathan, S., 42
Randesi, M., 141
Rangaswamy, M., 126, 150
Rapee, R., 134
Rasetti, R., 48, 142
Rauch, A., 48
Ravindran, A., 111
Raychaudhuri, S., 28
Reddy, J., 86
Rees, E., 15, 80, 171
Reich-­‐Erkelenz, D., 116
Reimers, M., 22
Reinvang, I., 93
Reitschel, M., 15
Ren, B., 45
Ressler, K., 36
Rex-­‐Haffner, M., 123
Rice, J., 126
Richards, A., 73
Richardson, T., 50
Richter, M., 139
Rickels, K., 50
Riemers, M., 165
Rietschel , M., 85
Rietschel, M., 7, 16, 32, 59,
72, 87, 91, 120, 122, 137,
180
Rijpkema, M., 175
Rijsdijk, F., 112
Riley, B., 62, 98, 165
Rimol, L., 120
Riolo, R., 157
Ripatti, S., 76, 153
Ripke, S., 28, 52, 60
Rivera Angles, M., 186
Rivera, M., 96, 191
Roberts, G., 4
Robertson, G., 50
Robison, R., 70
Roeyers, H., 74
Roffman, J., 140
Rogdaki, M., 45
Rónai, Z., 134, 136
Ronald, A., 174
Roncada, P., 50
Rose, E., 20
Rose, R., 146
Rosenberg, D., 139, 140
Rosenfeld, J., 54, 96
Ross, C., 30
Rossin, E., 28
Rostami, M., 172
Rothenberger, A., 74, 113
Roubeson, M., 25
Roussos, P., 32, 114
Rouvinen-­‐Lagerström, N.,
155
Royers, H., 113
Rubin, L., 141
Rudd, D., 101
Ruderfer, D., 15, 16, 27, 56,
62, 80, 101, 129
Rudolf, G., 23, 44
Ruggeri, B., 158
Ruggeri, M., 157
Rujescu, D., 16, 37, 136
Russell, E., 138
Russo, G., 136, 175
Ruttorf, M., 137
S
Saccone, N., 147
Sadee, W., 18
Saemann, P., 52
Saetre, P., 171
Sagvolden, T., 65
Saito, M., 31
Saitoh, O., 118
Sajeev, G., 200
Sakata, S., 145, 192
Salah, H., 178
Salisbury, D., 112
Salk, R., 119
Salminen, O., 153
Salomaa, V., 94, 138
Salum, G., 131
Samaan, Z., 96
Sämann, P., 9
Sambataro, F., 142
Samocha, K., 28
Sanchez, M., 182
Sanders, A., 53, 79, 94
Sanders, S., 25
Sandman, N., 94
Sanjeev, J., 152
Sano, A., 81
Santangelo, S., 172
Sarin, S., 153
Sarkozy, P., 123, 166
Sasaki, T., 84
Sasanfar, R., 172
Sasikala, K., 107
Sasvári-­‐Székely, M., 123,
134, 136, 166, 195
Sathyan, P., 161
Sattlecker, M., 194
Savage, A., 164
Saviouk, V., 87
Savolainen, K., 190
Sawa, A., 122
Schaid, D., 49
Schalkwyk, L., 186, 187
Schalling, M., 62, 130, 135
Scheet, P., 29
Scheftner, W., 31
Schellenberg, G., 26
Scherer, S., 24
Schlessinger, D., 72
Schmäl, C., 72
Schmidt, K., 58
Schmidt, M., 52
Schoenauer, S., 137
Schork, N., 66, 121
Schubart, C., 182
209
Schubert, M., 180
Schuch, I., 131
Schuckit, M., 126, 148, 150
Schulz, A., 169
Schulze, K., 112
Schulze, T., 15, 32, 59, 72,
116, 120, 122, 180, 201
Schumann, G., 43, 143, 158
Schuroff, F., 68
Schwab, S., 81, 82
Schwahn, C., 169
Schweitzer, R., 5
Scolnick, E., 62
Scott , D., 152
Scott, A., 82
Sebat, J., 15
Sedvall, G., 171
Seidman, L., 118, 121
Seneviratne, C., 160, 161
Sergeant, J., 74
Serre, T., 31
Serretti, A., 145, 156, 162,
187, 197, 198
Severino, G., 50
Shah, A., 65
Shaham, Y., 164
Shaikh, S., 201
Sham, P., 28
Sharma, B., 147
Sharma, R., 149
Shekhar, A., 66
Shekhtman, T., 39
Shen, Q., 71
Shen, Y., 131
Shenton, M., 118
Sher, K., 56
Shi, J., 31, 53
Shinkai, T., 145, 192
Shirtcliff, E., 126
Short, S., 19
Shugart, Y., 99
Siburian, R., 172
Sidoti, A., 187
Siegel, S., 34
Siever, L., 78
Sigurdsson, E., 16
Silander, K., 155
Silva, A., 189
Silveira, P., 131
Silverman, J., 78
Sims, R., 60
Sinclair, D., 155
Singh, S., 90, 151
Sinopoli, V., 140
Sipilä, T., 6, 76
Skjødt, C., 129
Sklar, P., 15, 16, 31, 47, 55,
56, 59, 62, 73, 76, 80, 89,
97, 101, 129
Skrobot, O., 199
Smeets, H., 176
Smit, J., 87
Smith, C., 110
Smith, R., 18, 84
Smoller, J., 112, 129, 140
Snyder, K., 49
Snyder, L., 197
Soeiro-­‐de-­‐Souza, M., 114
Soggiu, A., 50
Soliman, F., 36
Somers, M., 117
Sommer, I., 117, 182
Somogyi, A., 195
Song, J., 133, 177
Soria, V., 132
Souery, D., 197
Soundy, T., 196, 200
Souza, R., 201
Sprooten, E., 116, 141
Squassina, A., 50
Srinivas, L., 170
St Clair, D., 16, 73
Stallings, M., 156
State, M., 25
Stathias, V., 63
Steele, C., 59
Steen, V., 85, 93
Stefanson, H., 16
Stefansson, H., 15, 78
Stefansson, K., 15, 16
Steffens, M., 87
Steinberg, S., 16, 78
Steinhausen, H., 74, 113
Stephens, S., 147
Stergiakouli, E., 74
Stewart, A., 61, 194
Stone, W., 121
Stowe, Z., 123
Straub, R., 33
Strauss, J., 102, 191
Strengman, E., 125
Stringer, S., 58
Strohmaier, J., 32, 72, 85,
87, 122
Stürmer, T., 122
Subhashree, D., 160
Suda, S., 124, 183
Suderman, M., 38
Sulkava, S., 137
Sullivan, P., 44, 53, 55, 56,
62, 76, 89, 91, 97, 98, 99,
100, 101, 170, 199
Sun, B., 193
Sun, J., 22, 23, 24
Sun, W., 91
Sundermann, E., 141
Suomi, S., 109
Sussmann, J., 116, 141
Sutcliffe, J., 26
Sutin, A., 72
Suzuki, M., 70, 75
Svenningsson, P., 45
Svensson, A., 173
Sweeney, C., 148
Syed, Z., 174
Szántai, E., 134
Szatkiewicz, J., 91, 99
Szekely, A., 123
Szyf, M., 38

T
Taj, R., 100
Takahashi, H., 118
Takata, A., 81
Takeda, M., 70, 75, 117, 118
Takei, N., 124
Talati, A., 166
Talbot, K., 34
Tang, P., 181
Tansey, K., 7
Tatsumi, M., 118
Taub, M., 122
Tavian, D., 145
Taylor, R., 152
Taylor, A., 99
Taylor, G., 112
Tee, S., 181
Telles Ribeiro, H., 178
Tenesa, A., 93
Teo, C., 102, 111, 154
Terenius, L., 171
Termorshuizen, F., 176
Terracciano, A., 72
Terwisscha van Schel, A.,
130
Tesli, M., 120
Teumer, A., 169
Thakkar, M., 149
Thapar, A., 74
Theall, K., 112
Theberge, F., 164
Thennarasu, K., 160
Thiagalingam, S., 109
Thimm, M., 32
Thiselton, D., 62
Thomas, G., 104
Thompson, S., 31
Thomsen, J., 175
Thurin, K., 142
Thygesen, J., 129
Tian, Q., 83
Tinsley, C., 20
Tischfield, J., 126, 148, 150
Tiwari, A., 40, 48, 158, 200,
201, 202
Tobar, S., 178
Tokunaga, K., 84
Tolouei, A., 172
Tomblin, B., 193
Tommerup, N., 176
Toner, D., 129
Tooney, P., 92
Torma, N., 166
Tornador, C., 80
Torri, F., 88
Tosato, S., 16, 157
Tosto, M., 128
Tovilla-­‐Zarate, C., 182, 186
Toyota, T., 81
Tozzi, F., 191, 200
Treutlein, J., 72
Tropeano, M., 134
Trujillano, D., 80, 184
Tsivtsivadze, E., 26
Tsuang, D., 78
Tsuang, M., 69, 121
Tsutsumi, A., 69, 82
Tümer, Z., 176
Tunc-­‐Skarka, N., 120
Turecki, G., 8, 37, 38
Tzvetkov, M., 116
U
Ueno, M., 188
Uher, R., 7, 127, 186
Ujike, H., 75
Urban, A., 102
Urban, R., 166
Urretavizcaya, M., 132
Ursano, R., 185
Utge, S., 138, 177
Utsunomiya, K., 145, 192
V
V., N., 170
Vakkalanka, R., 83
Valero , J., 132
Vallada, H., 165
Valle, D., 104, 122
Vallender, E., 148
Valli, K., 94
van 't Slot, R., 117
van Beek, J., 29
van Beijsterveldt, T., 29
van de Lagemaat, L., 16
van den Oord, E., 23, 44, 53,
88, 170, 199
van der Meere, J., 113
van der Wee, N., 115
van Duijn, C., 87
van Eijk, K., 117
van Gastel, W., 182
van Haren, N., 130
Van Hulle, C., 126
van Tol, M., 115
Vandever, J., 156
VanWijk, R., 70
Varga, G., 123, 136
Vargas, I., 125
Vargas, L., 125
Varghese, M., 142
Vasiliou, S., 164
Vasquez, A., 175
Vassos, E., 72
Vazquez, V., 139
Vedernikov, A., 58
Veltman, D., 115
Ventura, S., 44
Vereczkei, A., 195
Veres-­‐Székely, A., 136
Verhage, M., 26
Videtič Paska, A., 173
Vieten, C., 143
Vilella , E., 132
Villar Soto, M., 182
Vincent, J., 191
Vink, J., 29
Visscher, P., 73
Vivek, B., 152
210
Vladimirov, V., 62
Voineskos, A., 48
Vorstman, J., 128
Vreeburg, S., 115
Vuokko, K., 153
W
Waldman, I., 93, 179
Walsh, D., 98, 165
Walter, H., 32
Walters, J., 136, 138
Wang, J., 126, 150
Wang, K., 70
Wang, L., 24, 198
Wang, S., 151
Wang, T., 104
Wang, W., 91
Wang, X., 92, 161
Wang, Y., 71, 198
Warburton, A., 164
Wassink, T., 101
Watson, A., 64, 178
Webb, B., 98, 146, 148, 165
Weber, K., 141
Webster, M., 55, 185
Wedenoja , J., 153
Wegener, G., 45, 175
Weinberger, D., 33, 48, 83,
142
Weinfeld, M., 121
Weinshilboum, R., 49
Weissman, M., 31, 166
Weissman, S., 102
Wendland, J., 55, 59
Werge, T., 16, 120, 129, 171
Werme, M., 45
Wessa, M., 32
Whalley, H., 141
White, M., 142
Whitfield, J., 124
Wickramaratne, P., 166
Wigg, K., 45
Wijsman, E., 78
Wilcox, H., 5
Wildenauer, D., 81, 82
Wildenauer, M., 81
Wilhelmsen, K., 143
Wilkinson, L., 42
Willemsen, G., 29
Williams, C., 152
Williams, H., 84, 86, 136
Williams, J., 60
Williams, N., 74, 97
Williams, R., 149, 167
Williams, S., 61, 194
Winchester, C., 77
Winkler, A., 47
Winn, M., 121
Wirgenes, K., 120
Witasp, A., 45
Witt, S., 32, 120, 122, 137
Wiuf, C., 95, 169, 180
Wolf , C., 85
Wolf, I., 120
Wong, C., 158
Woo, T., 118
Wood, J., 178
Woudstra, S., 115
Wray, N., 58, 73, 124
Wright, A., 4
Wright, E., 151
Wright, M., 124
Wu, J., 92
Wu, K., 140
Wu, R., 70
Wu, Y., 193
Wüst, S., 122
Xavier, R., 28
Xiao, X., 29
Xie, W., 45
Xing, G., 185
Xing, J., 70
Xiong, M., 99
Xu, F., 22
Xu, J., 22, 24
Xu, Q., 131
Xu, X., 193
X
Y
Yamada, K., 81, 124, 145,
192
Yamamori, H., 117, 118
Yan, J., 148
Yandell, M., 70
Yang, L., 70
Yang, X., 70
Yassin, A., 178
Yasuda, Y., 70, 117, 118
Yemmiganur Chandrash, J.,
179
Yeo, A., 200
Yilmaz, Z., 113
Yolken, R., 180
Yoneda, H., 69, 82
Yoshikawa, T., 81, 124
Yoshimi, A., 70, 75
Young, S., 156
Young-­‐Wolff, K., 153
Yu, C., 78
Yu, H., 133
Yuan, Q., 71, 109
Z
Zaharieva, I., 74
Zai, C., 102, 113, 154, 158,
200, 201
Zai, G., 139, 158
Zandi, P., 31, 54, 95, 104
Zanoni, M., 157
Zeanah, C., 112
Zeggini, E., 98
Zeledon, M., 122
Zemojtel, T., 88
Zhang, C., 21, 22
Zhang, F., 48
Zhang, J., 131, 198, 202

Zhang, L., 151, 185
Zhang, P., 70
Zhang, Y., 22, 102
Zhang-­‐James, Y., 65
Zhao, Q., 71, 198
Zhao, Z., 22, 23, 24
Zheng, D., 65
Zhou, Z., 71, 109
211
Zhu, S., 30
Zhu, X., 102
Zitman, F., 115
Zlojutro, M., 46, 103
Zohar, J., 197
Zsanett, T., 191
Zsofia, N., 191
Zupanc, T., 173

Please join us for these
Future Events:
XX th World Congress of Psychiatric Genetics
October 14-18, 2012
Hamburg, Germany
XXI st World Congress of Psychiatric Genetics
October 17-21, 2013
Boston, Massachusetts, USA
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