IMS Magazine - Summer 2012 edition in PDF format - Institute of ...

FEATURE
necessary strategy for collecting sufficiently
large psychiatric patient samples for genetic
analysis, they can introduce new problems
such as the imprecision in measuring psychiatric
“phenotypes”. It is not clear that ADHD
or any other psychiatric disorder is assessed
and diagnosed in exactly the same way in
Brazil as it is in the Netherlands. Moreover,
global studies collect DNA from very divergent
ethnic groups. It is entirely possible
that the genetic risks for a common disease
may not be identical in every ethnic group.
Based on these limitations, it was clear to us
that novel methods were needed to break this
impasse.
Crosbie: Endophenotypes 6 , which are objective,
quantitative, and heritable “intermediate
phenotypes” or “biological markers”,
provide increased power to genetic studies
by pointing to a more homogeneous genetic
group of individuals and measuring a process
that is closer to the underlying genetic
mechanism. There is evidence that response
inhibition, which refers to the ability to stop
a speeded motor response and can be measured
by the SST, is a valid endophenotype
for ADHD based on the results of clinical,
family, functional imaging and preliminary
genetic investigations (response inhibition
influenced by the genetic risk factors that influence
ADHD) 2,7 .
Paul Arnold, MD, PhD
Russell Schachar, MD, FRCP(C)
Schachar: At that point, we will also generate
animal models and learn more about the proteins
that these genes play a role in.
Q How will this study contribute to the
field of psychiatric genetics?
Schachar: There is a great deal of enthusiasm
about the use of cognitive endophenotypes or
biomarkers in psychiatric genetic research.
Ours will be one of the first to be completed.
If it proves to be useful in identifying genetic
risks for inhibition and for these disorders,
the field will move rapidly.
Crosbie: With this potential to point to new
candidate genes of interest for ADHD and
OCD, the study may provide us with novel
information about the etiology and molecular
pathways of these disorders, as well as
further our understanding of other neuropsychiatric
disorders.
Arnold: Our approach with TAG is consistent
with previous work suggesting that we
should be thinking of neuropsychiatric disorders
as continuous rather than categorical
traits. If we are successful in identifying risk
variants for psychiatric disorders, others may
want to adopt a similar strategy of studying
large general population samples rather than
focusing solely on clinic-based populations.
Investigator photos by Brett Jones
Arnold: The general population-based design
of TAG provided a quick and cost-effective
way to collect a large sample of children
using a single and uniform assessment of
behavioural (ADHD, OCD, and other conditions
through questionnaire), cognitive (response
inhibition measured by SST) and genetic
(saliva DNA) traits. With this data, we
are able to draw from the full range of variation
in our traits of interest, and use an extreme
trait approach 8 to conduct a genomewide
association study comparing children
in the upper and lower extremes of specific
behavioural and cognitive traits.
Q What are the objectives of TAG?
Arnold: Once we have performed our
GWAS and identified interesting risk variants,
we intend to genotype these variants
in our entire sample and clinical samples.
By taking our results to clinical samples, we
can test if the identified variants [in the general
population] are also found in ADHD or
Jennifer Crosbie, PhD, CPsych
OCD patients, and also look for associations
with interesting phenotypes we can’t measure
in the general population (e.g. neuroimaging).
Another future direction is to look for
other genetic variations beyond the common
“single nucleotide polymorphisms” surveyed
in GWAS. For example, we will analyze copy
number variants and relatively rare but functional
single nucleotide variants found in
coding regions of genes.
References
1. Neale BM, et al. Meta-analysis of Genome-wide Association
Studies of Attention-Deficit/Hyperactivity
Disorder. J Am Acad Child Adolesc Psychiatry.
2010;49:884-897.
2. Crosbie J, et al. Validating Psychiatric Endophenotypes:
Inhibitory Control and Attention Deficit Hyperactivity
Disorder. Neurosci Biobehav Rev. 2008;32:40-
55.
3. Pauls DL. The Genetics of Obsessive Compulsive Disorder:
A Review of the Evidence. Am J Med Genet C Semin
Med Genet. 2008;148:133-139.
4. Boileau B. A Review of Obsessive-Compulsive Disorder
in Children and Adolescents. Dialogues Clin Neurosci.
2011;13:401-411
5. Menzies L, et al. Neurocognitive Endophenotypes of
Obsessive-Compulsive Disorder. Brain. 2007;130:3223-
3236.
6. Gottesman II, Gould TD. The Endophenotype Concept
in Psychiatry: Etymology and Strategic Intentions.
Am J Psychiatry .2003;160:636-645.
7. Schachar RJ, et al. Heritability of response inhibition
in children. J Int Neuropsychol Soc. 2011; 17(2):238-47.
8. Liu DJ, Leal SM. A Unified Framework for Detecting
Rare Variant Quantitative Trait Associations in Pedigree
and Unrelated Individuals via Sequence Data. Hum
Hered. 2012;73:105-122.
IMS MAGAZINE SUMMER 2012 GENOMIC MEDICINE | 20