2009 Vienna - European Society of Human Genetics

Complex traits and polygenic disorders
P09.019
Role of serotonin transporter promoter length polymorphism in
autism: A south African population based study
Z. Arieff, M. Kaur, H. Gameeldien, M. Davids;
University of the Western Cape, Bellville, South Africa.
The serotonin transporter promoter length polymorphism (5-hydroxytryptamine
transporter length polymorphism, 5-HTTLPR) has long
been implicated in autism and other psychiatric disorders. The use of
selective serotonin reuptake inhibitors (SSRIs) have shown to have
a positive effect in treating some symptoms of autism. The effects of
these drugs vary in individuals due to the presence of S or L alleles
of 5-HTTLPR. Studies performed on various autistic populations have
found different allele frequencies for the L and S alleles. In the present
study, allelic frequencies and genotypes of 110 South African (SA) autistic
individuals (21 African, 48 Mixed and 41 Caucasian) were determined
and compared with the matching SA ethnic control populations.
The S/S genotype was found to be highly significantly associated with
all the SA autistic ethnic populations namely, Caucasian, χ2 = 11.078;
Mixed, χ2 = 18.512 and total group, χ2 = 46.712 (df = 2; p < 0.001).
A highly significant increase in the S allele of the Mixed autistic group
( χ2 = 14.877, p < 0.001, df = 1) and the total autistic group ( χ2 =
17.742, p < 0.001, df = 1) was found when compared to the matching
control groups. The comparison of our data with studies of other autistic
populations round the world showed highly significant differences
in allele numbers to French, Germans, Israelis, Portuguese and the
Americans (p < 0.005). It was less significant for the second French
group, Japanese and Korean populations (p < 0.05) and no difference
was observed between the Indian autistic population. This is the first
SA study of autistic individuals of different ethnic backgrounds showing
significant differences of the allele and genotype frequencies of the
5-HTTLPR.
P09.020
Identification of novel X-linked functional variants associated
with autoimmune thyroid diseases
S. I. Gulsuner 1 , S. Gullu 2 , T. Ozcelik 1 ;
1 Department of Molecular Biology and Genetics, Bilkent University Faculty of
Science, Ankara, Turkey, 2 Department of Endocrinology and Metabolic Diseases,
Ankara University, School of Medicine, Sihhiye, Ankara, Turkey.
Autoimmune thyroid diseases (AITDs) are more prevalent in females.
We observed that a significant proportion of females diagnosed with
AITDs display extremely skewed X chromosome inactivation (XCI) ratios
in their blood cells (Eur. J. Hum. Genet. 14; 791-97, 2006). “Loss of
mosaicism” for X-linked gene expression could be the first step of the
cellular events that lead to the breakdown of self-tolerance in females.
We propose that co-inheritance of two distinct events on the X: mutations
that cause skewed XCI, and heterozygosity for non synonymous
polymorphisms in as yet unknown but critically important genes could
contribute to autoimmune processes. This hypothesis was tested with
a custom made Affymetrix 5K microarray that we designed, which contained
all known coding SNPs on the X, as well as intronic SNPs with
high heterozygosity ratios. In addition, 166 autoimmunity associated
autosomal SNPs (Nature 447; 661-78, 2007; Nat. Genet. 39; 857-
64, 2007) were printed on the same microarrays. 84 female patients
and 248 female controls with known XCI profiles were genotyped.
The strongest associations were at nonsynonymous SNPs in TFDP3
[OR: 3.44(95% CI:1.62-7.29; p=0.00067)], ZMAT [OR: 2.22(95% CI:
1.23-3.66; p=0.003)], and C1GALT1C1 [OR:2.59(95% CI:1.16-2.59;
p=0.006)]. Autosomal SNPs with significant associations were in
SH2B3 [OR:2.03(95% CI: 1.42-2.91; p=000088)] and C12orf30 [OR:
1.99(95% CI: 1.39-2.85; p=0.00016)]. We note that X-linked SNPs
reported here were not represented in the commercially available genome-wide
association study platforms. These results suggest that the
X chromosome could be critically important in female predisposition to
AITDs. This work is supported by TUBITAK-SBAG-3334 grant.
P09.021
copy Number Variation in Bipolar Affective Disorder
D. Grozeva 1 , G. Kirov 1 , N. Norton 1 , D. Ivanov 2 , M. Owen 1 , M. O’Donovan 1 , N.
Craddock 1 ;
1 Department of Psychological Medicine, Cardiff University, Cardiff, United
Kingdom, 2 Biostatistics and Bioinformatics Unit, Department of Psychological
Medicine, Cardiff University, Cardiff, United Kingdom.
Copy number variation (CNV) in the human genome is very common
and may play an important role in disease susceptibility. The role of
CNVs in bipolar disorder (BD) has been largely unknown, in contrast to
other common neuropsychiatric disorders, such as autism and schizophrenia,
where a clear role for CNVs has been established in multiple
publications.
The objective of the current study is to determine whether large
(>100kb) and rare (found in 1Mb in size, when compared to both to the bipolar patients,
or the same group of controls.
These results suggest that large rare CNVs may not play a substantial
role in developing BD, unlike their confirmed role in schizophrenia and
autism. This probably reflects the complex nature of the underlying
genetic components leading to susceptibility to BD, involving many
genes and genetic variants. CNV platforms with higher resolution and
quality should be used to investigate the role of smaller CNVs in BD.
P09.022
Genes for elite bodybuilder status
I. I. Ahmetov, A. M. Hakimullina, S. E. Khalchitskiy, R. R. Dondukovskaya, V.
A. Rogozkin;
St Petersburg Research Institute of Physical Culture, St Petersburg, Russian
Federation.
Genetic influence on power performance and extremity circumferences
is suggested by family and twin studies. The aim of the present
study was to reveal an association between AMPD1 (regulates AMP
metabolism) C34T, PPP3R1 (involved in hypertrophic response) 5I/5D,
PPARG (regulates lipid metabolism) Pro12Ala, VEGFA (activates angiogenesis)
G-634C gene polymorphisms and several physiologic
and anthropometric parameters in bodybuilders. The study involved
21 highly elite male bodybuilders (World and Europe Championship
winners and participants). Subjects were questioned about their best
results in powerlifting squat, bench press and deadlift. For muscularity
estimation four extremity circumferences were measured: extended
upper arm (EAC), forearm (FC), calf (CC), and thigh (TC). Genotyping
for the gene variants was performed by polymerase chain reaction
and restriction enzyme digestion. We found that VEGFA C allele
(with higher transcriptional activity) carriers exhibited the greatest relative
muscle mass (CC/GC - 57.9 (3) %, GG - 53.9 (4.2) %; P=0.03).
PPP3R1 5D allele (known as hypertrophy-related allele) was associated
with biggest values of EAC (5I/5D - 44 (5.5) cm, 5I/5I - 38.9 (3.7)
cm; P=0.029). AMPD1 CC homozygotes demonstrated greater results
in deadlift than carriers of mutant (null) T allele (CC - 245 (42) kg, CT
- 180 (0) kg; P=0.049). Thus, the presence of AMPD1 C, VEGFA C and
PPP3R1 5D alleles are associated with greater power performance
and muscle mass gain in elite bodybuilders.
P09.023
Analysis of variation in the canine melanocortin-4 receptor gene
(mc r)
L. van den Berg 1,2 , S. M. van den Berg 3,4 , E. E. C. P. Martens 3 , H. A. W. Hazewinkel
3 , N. A. Dijkshoorn 5 , H. A. Delemarre-van de Waal 1 , P. Heutink 6 , P. A. J.
Leegwater 3 , H. C. M. Heuven 3 ;
1 Leids Universitair Medisch Centrum, Leiden, The Netherlands, 2 Department
of Human Genetics, Leids Universitair Medisch Centrum, Leiden, The Netherlands,
3 Department of Clinical Sciences of Companion animals, Utrecht University,
Utrecht, The Netherlands, 4 Faculty of Behavioral Sciences, University of
Twente, Twente, The Netherlands, 5 Orthopedic Research Foundation, Dierenartsenpraktijk
Dijkshoorn, Zeist, The Netherlands, 6 Department of Clinical Genetics,
section Medical Genomics, VU University Medical Center, Amsterdam,
The Netherlands.
The melanocortin-4 receptor plays a central role in the regulation of
energy balance in humans and other species. Rare mutations in the
coding region of the gene encoding this receptor (MC4R) are the lead-