European Human Genetics Conference 2007 June 16 – 19, 2007 ...

Genetic analysis, linkage, and association
P1107. Association analysis of the triallelic polymorphism of the
serotonin transporter gene with suicide
Z. Khalilova, D. Gaysina, E. Khusnutdinova;
Institute of Biochemistry and Genetics, Ufa, Russian Federation.
Serotonergic dysfunction has been implicated in the pathophysiology
of suicidality. The serotonin transporter (5-HTT) strongly modulates serotonin
function and is a major therapeutic target in several psychiatric
diseases, including anxiety, depression, and suicide. 5-HTTLPR, a
functional polymorphism of the 5-flanking region of the 5-HTT gene has
been intensively studied for association with suicidal behaviour. Some,
but not all, studies using biallelic S/L genotyping have demonstrated a
higher frequency of the low activity S allele and with suicidal behavior.
A>G polymorphism (rs25531) has been detected within 5-HTTLPR:
L G haplotype is equivalent to the lower expressing S allele. The aim
of our study was to examine the relationship of a triallelic 5-HTTLPR
polymorphism to suicidal behavior in a gender-specific manner. 231
suicide attempters (79 men, 152 women) and 264 healthy volunteers
(160 men, 104 women) without history of suicidal behaviour from the
general population of Russia were genotyped for the triallelic 5-HT-
TLPR polymorphism using PCR-RFLP technique. All individuals were
considered as LL carriers (L A L A ), LS carriers (L A S, L A L G ) or SS carriers
(SS, L G S, L G L G ). The distribution of allelic and genotype frequencies
were in accordance with the Hardy-Weinberg equilibrium. We revealed
no significant differences in allele and genotype distribution between
suicide and control groups. In women there was a tendency of a lower
frequency of the LS carriers in suicide group compared to that in control
group (chi2=3.5; p=0.06; OR=0.62, 95%CI 0.38-1.02). Our findings
indicate a possible contribution of the 5-HTT gene to susceptibility for
suicidal behaviour in females only.
P1108. Analysis of type I collagen α1 and α2 chains genes in
patients with syringomyelia from Bashkortostan
T. N. Mirsaev 1 , D. V. Islamgulov 2 , E. K. Khusnutdinova 2 ;
1 Bashkir State Medical University, Ufa, Russian Federation, 2 Institute of Biochemistry
and Genetics of Ufa Scientific Center of RAS, Ufa, Russian Federation.
Syringomyelia is a rare disease of the spinal cord that causes neurological
deficit. A mendelian transmission of syringomyelia (autosomal
dominant or recessive) has been proposed in approximately 2% of
reported cases. The association of syringomyelia with hereditary diseases
(Noonan’s syndrome, phacomatoses) has been mentioned frequently
in the literature. However the possible involvement of a genetic
component in some cases of syringomyelia is debated. In Bashkortostan
republic syringomyelia rate is one of the highest around the world
(3.2 - 130 cases per 100 000 inhabitants).
The aim of the present study was to test two polymorphisms in genes
encoding proteins of α1 and α2 chains of collagen (A/MspI of the Col1A1
gene, B/MspI of the Col1A2 gene) for association with syringomyelia
in patients from Bashkortostan. 132 patients presented with magnetic
resonance imaging (MRI)-proven syringomyelia and 196 controls
were typed for the above-mentioned gene variants using polymerase
chain reaction technique.
Our data indicate the contribution of Col1A1*A (p=0.013, OR=1.28,
95%CI=1.07-1.99) and Col1A2*N (p=0.011, OR=1.37, 95%CI=1.12-
2.03) alleles to susceptibility for syringomyelia in samples from
Bashkortostan. Further analysis showed overrepresentation of the
Col1A1*A/*A (p=0.023, OR=1.6, 95%CI=1.05-1.59) and Col1A2*N/*N
(p=0.007, OR=1.96, 95%CI=0.75-2.4) genotypes among patients
compared to controls and these genotypes can be possible markers
of syringomyelia.
Advances in knowledge about the genetic basis of syringomyelia offer
the prospect of developing new approaches to treatments of this disorder.The
work was supported by RSCI grant #05-06-06168a.
P1109. Association of Interferon Regulatory Factor 5 (IRF )
polymorphisms with systemic lupus erythematosus (SLE)
H. Siu 1 , W. L. Yang 1 , C. S. Lau 2 , T. M. Chan 2 , H. S. Wong 1 , Y. L. Lau 1 , M. E.
Alarcon-Riquelme 3 ;
1 Department of Paediatrics and Adolescent Medicine, University of Hong Kong,
Queen Mary Hospital, Hong Kong, Hong Kong, 2 Department of Paediatrics and
Adolescent Medicine and Medicine, University of Hong Kong, Queen Mary Hospital,
Hong Kong, Hong Kong, 3 Department of Genetics and Pathology#, Unit of
Medical Genetics, Rudbcek Laboratory, Uppsala University, Uppsala, Sweden.
Background:
Systemic lupus erythematosus (SLE) is a complex autoimmune disease
characterized by the dysfunction of immune cells, leading to hyperactivity
of B cells and over-production of autoantibodies and the
formation of immune complexes.
The level of IFN-α, a type I interferon, is correlated with both SLE disease
activity and severity, and is therefore suggested to be involved in
the pathogenesis of SLE. Activation of transcription factors, including
Interferon Regulatory Factors (IRFs) 3, 5 and 7 can modulate the expression
of type I IFN genes. IRFs control inflammation, immunity and
apoptosis. Irf5 knockout mouse also shows reduction of pro-inflammatory
cytokines, including IL-6, IL-12 and TNF-a production. Recently
several association studies in different populations have reported that
IRF5 gene is a susceptibility gene of SLE.
Methods:
We hypothesized that polymorphisms of IRF5 may affect the susceptibility
and severity of SLE in the Hong Kong Chinese population. SNP
rs2004640 creates a 5’ donor splice site for alternate isoform of transcript
in exon 1, whereas rs10954213 creates a functional polyadenylation
site in 3’ UTR and affects the expression of transcript variants.
The 2 SNPs were genotyped in 444 SLE patients and 410 healthy
controls, using sequencing.
Results:
No association of IRF5 gene polymorphisms with SLE was found. However,
an overall difference in the distribution of the haplotype frequencies
between SLE patients and controls was detected. The haplotype
TA was identified as a probable risk haplotypes associated with SLE.
P1110. Association study of the GABA A cluster on 15q11-13 with
Tourette Syndrome in the French Canadian population.
J. Riviere 1 , Y. Dion 2 , P. Lesperance 1 , G. Tellier 3 , F. Richer 1 , S. Chouinard 1 , G.
A. Rouleau 1 ;
1 CHUM Research Centre, Montreal, PQ, Canada, 2 McGill University Health
Centre, Montreal, PQ, Canada, 3 Sainte Justine Hospital, Montreal, PQ, Canada.
Tourette Syndrome (TS) is a complex neuropsychiatric disorder manifested
by motor and vocal tics and often associated with behavioral
abnormalities. Various neurotransmitters involved in the cortico-striatal-thalamo-cortical
circuits have been implicated in TS, including the
dopaminergic, glutamatergic, GABAergic, serotonergic, and noradrenergic
systems. However, most of the genetic studies have focused on
candidate genes implicated in dopamine neurotransmission. The goal
of this study was to investigate the genetic association between single
nucleotide polymorphisms (SNPs) in the cluster of GABA A receptor
subunit genes on 15q11-13 and TS in the French Canadian (FC) population.
This region has been consistently implicated in several neurodevelopmental
disorders and behavioral abnormalities.
With an average spacing of 33 Kb, 26 SNPs spanning the GABA A receptor
subunit genes (GABRB3, GABRA5, GABRG3) were selected
based on minor allele frequency >0.1, spacing and haplotype blocks.
We performed a family-based association study by typing these SNPs
in 212 FC trios with TS. Transmission/disequilibrium test (TDT) and
haplotype analyses of various SNP-windows were performed using
the TDTPHASE program. Because these genes may be subject to
genomic imprinting, we also performed analyses of transmission by
parental sex.
TDT of individual markers and haplotype analyses did not provide
positive association results. When analyzed separately, paternal and
maternal transmissions provided various p values < 0.05, but these
results did not remain significant after correction for multiple testing.
These data suggest that the GABA A cluster on 15q11-13 is not a susceptibility
locus for TS.
P1111. Use of SNP array analyses for diagnosis of autosomal
recessive heterogeneous diseases : identification of the second
TRIM32 mutation in limb-girdle muscular dystrophy type 2H
M. Cossée 1,2 , C. Lagier-Tourenne 1,3 , C. Tranchant 4 , C. Seguela 1 , F. Leturcq 5 , V.
Biancalana 1,6 , N. Dondaine 1 , C. Stoetzel 6 , J. Chelly 5 , E. Flori 7 , H. Dollfus 2,6 , M.
Koenig 1,3 , J. Mandel 1,3 ;
1 Laboratoire de diagnostic génétique, Hôpitaux Universitaires de Strasbourg,
Strasbourg, France, 2 Service de génétique médicale, Hôpitaux Universitaires
de Strasbourg, Strasbourg, France, 3 IGBMC (CNRS/INSERM/ULP), Illkirch,
2