2008 Barcelona - European Society of Human Genetics

Normal variation, population genetics, genetic epidemiology 0
amount of other genetic variants and the larger samples are needed to
be tested before its decline .
P07.029
Natural Background Radiation Dictates Extensive structural
Polymorphism in the Human Y-chromosome
S. Premi, J. Srivastava, S. Ali;
National Institute of Immunology, Delhi, India.
Ionizing radiations are known to affect the human genome but its impact
on human Y chromosome still remains unaddressed . Here we
analyze 300 males residing in an area containing the world’s highest
level of natural background radiation (NBR) and 390 controls from different
parts of India . Random microdeletions were observed in 95%
of the NBR exposed males with higher frequency in AZFc region but
without gr/gr or b2/b4 phenotypes . Scrutiny of the male fertility associated
genes showed copy number polymorphism (CNP) and tandem
duplication in 84%, and exclusive deletion of DBY in 25% of the exposed
males . Detailed analysis revealed multiple polymorphic copies
of SRY and CDY1 genes in addition to several known and novel mutations
of the SRY gene . Amongst NBR exposed males with multiples
copies of the DAZ genes, 75% showed varying FISH signals for DAZ
genes with unilocus or bilocus duplications whereas 30% showed
mosaicism in terms of presence/absence of the signals in 6-8% cells
and unexpected number of signals in 9-12% interphase nuclei . Interestingly,
all these alterations were exclusively somatic in nature substantiating
normal fertility status of NBR exposed males . Though the
actual mechanism is not known, we hypothesize that some putative
innate protective mechanisms are operative in germline to counteract
the effect of NBR . Analysis of additional Y linked loci may uncover the
overall impact of NBR on the structural and functional attributes of this
chromosome .
P07.030
Genome-wide screen for copy number variation in a Finnish
schizophrenia case-control sample identifies a submicroscopic
deletion in 22q
O. P. H. Pietiläinen 1 , T. Paunio 1,2 , A. Tuulio-Henrikksson 3,4 , J. Suvisaari 3 , J.
Haukka 3 , T. Varilo 1 , K. Rehnström 1 , E. Jakkula 1 , A. Loukola 1 , J. Wedenoja 1 , S.
Ripatti 1 , M. Jussila 1 , J. Del-Favero 5,6 , J. Lönnqvist 2,3 , H. Stefansson 7 , L. Peltonen
1,8 ;
1 FIMM, Institute for Molecular Medicine Finland and National Public Health
Institute, Helsinki, Finland, 2 Unversity of Helsinki and Helsinki University Central
Hospital, Department of Psychiatry, Helsinki, Finland, 3 National Public Health
Institute, Department of Mental Health and Alcohol Research, Helsinki, Finland,
4 University of Helsinki. Department of Psychology, Helsinki, Finland, 5 Applied
Molecular Genomics Group, Department of Molecular Genetics, VIB, Belgium,
Helsinki, Finland, 6 University of Antwerp (UA), Antwerpen, Belgium, 7 deCODE
genetics, Reykjavik, Iceland, 8 Wellcome Trust Sanger Institute, Hinxton, Cambridge,
United Kingdom.
Copy number variations (CNV) are likely to comprise considerable
source for diversity in human genome and in determining heritable susceptibility
to diseases with complex etiology . We utilized Genome-wide
SNP-array data from Illumina 318K genotyping platform on a Finnish
sample of 200 familial schizophrenia cases and 200 controls with well
established genealogy to search for CNVs potentially predisposing to
schizophrenia . Half (47%) of the sample originated from an Internal
Isolate of Finland with an exceptionally high prevalence of schizophrenia
(3% versus 1 .2% for the general population) . The sample was a
part of a large international EU-funded consortium, SGENE, combining
1,454 schizophrenia patients and 1,600 controls of European origin.
In the Finnish sample we identified a novel 240-280 kb heterozygous
deletion in chromosome 22q11 .22 in 13 patients and three controls
all originating from the Isolate . We extended our investigations to
17,808 additional European population controls (2,525 from Finland)
and 1,254 cases of European origin including the rest of the SGENE
project . Among these individuals we found 29 carrying the deletion, 22
of which originated from the Isolate . In a Finnish schizophrenia family
sample we found 27/354 affected family members and 51/736 unaffected
family members carrying the deletion . One mentally retarded
individual was homozygous for the deletion . The deletion overlaps with
three genes, PPM1F, TOP3B and IGLV2-14, not previously linked to
schizophrenia. Our finding confirms the impact of population bottleneck
on the enrichment of large CNV and implies the impact of this 22q
region in the etiopathogenesis of familial schizophrenia .
P07.031
Analysis of normal human variation to identify mechanisms of
the monogenic disease, cystinosis
J. E. Curran, M. P. Johnson, M. A. Carless, H. H. H. Goring, J. Charlesworth,
K. Freed, T. D. Dyer, S. A. Cole, E. K. Moses, J. Blangero;
Southwest Foundation for Biomedical Research, San Antonio, TX, United
States.
Mutations in CTNS on 17p13 cause cystinosis, a rare autosomal recessive
disease characterized by defective transport of cystine out of
lysosomes . Using complex genomic approaches we studied the biology
of CTNS in large unaffected families assuming normal human variation
in CTNS expression could inform us about this gene’s function .
Using lymphocyte samples from 1240 individuals, we significantly detected
over 20,000 transcripts, including CTNS . To identify regulatory
variants, we resequenced CTNS in 191 founders, identifying over 180
SNPs for genotyping . Analysis of these variants with CTNS expression
revealed strong evidence for cis-regulation (p-values as low as 2 .4x10 -
39 ). We performed association analysis on the transcriptional profiles to
identify genes causally downstream of CTNS . Preliminary analyses revealed
multiple genes related to the mediation of polyglutamine tracts
and the unfolded protein response . To identify trans-acting upstream
genes influencing CTNS expression, we performed both genome-wide
linkage and association scans. Genome-wide linkage results identified
a region at 9q21 (p = 0 .0025) . Examination of the genetic correlations
of expression levels of genes within this region with CTNS expression
identified a novel candidate gene, VPS13A (vacuolar protein sorting
13A) . VPS13A and CTNS expression levels were inversely genetically
correlated (p = 9 ×10 -6 ), indicating VPS13A as a potential inhibitor
of CTNS expression . Sequence variation in VPS13A also influenced
CTNS expression (p = 0 .009) . Genome-wide association results identified
five additional trans-acting regions containing several reasonable
positional candidates . These results show the biological value of integrative
genomic and transcriptomic approaches for the identification of
disease gene function using normal human variation .
P07.032
CYP D genetic polymorphism in mexican Nahuas
M. López 1 , J. Guerrero 2 , R. Peñaloza 3 , L. Buentello 4 , F. Salamanca 3 , M.
Alonso 5 ;
1 Metropolitan Autonomous University, Mexico City, Mexico, 2 National Institure
of Neurology and Neurosurgery Manuel Velasco Suárez, Mexico City, Mexico,
3 Centro Médico Nacional Siglo XXI, Mexico City, Mexico, 4 Instituto de Investigaciones
Antropológicas, UNAM, Mexico City, Mexico, 5 National Institute of
Neurology and Neurosurgery, Mexico City, Mexico.
CYP2D6 catalyzes the metabolism of 25-33% clinically important
drugs and is highly polymorphic . There are at least 50 different alleles
of CYP2D6, which are correlated to ultrarapid, extensive and poor metabolizer
phenotypes . Interethnic differences in allele frequencies of
CYP2D6 have been documented for Europeans, Asians, Africans and
Hispanics; however data on Amerindians are scanty and limited to a
few populations . Nahuas are individuals that speak Nahuatl and comprise
the largest Mexican indigenous population . Nowadays, Nahuas
can be found at Mexico D .F . Southern area (central group) and in other
states (peripheral group) . In this study 315 donors representing 7 different
Nahua populations were genotyped for CYP2D6*3, CYP2D6*4,
and CYP2D6*10 by PCR-RFLP . Additionally, CYP2D6*17 was determined
in the Coyolillo group as previous data revealed a predominant
influence from African origin (Buentello-Malo, 2003). The frequency of
CYP2D6*3, 4, and 10 among 315 Nahuas was 1 .6%, 12 .2% y 1 .9%,
respectively; while CYP2D6*17 frequency was 32% in 36 Coyolillo
Nahuas . Allelic frequencies for each group are presented in the table
and compared to data from Mexican Mestizos (López, 2005). Our findings
show that Nahua groups are heterogeneous and different from
Mexican Mestizos . This study will extent the knowledge of the genetic
structure of Mexican Nahuas; in particular it could have important implications
for the use of drugs that are substrates of CYP2D6 and have
a narrow therapeutic index .