2008 Barcelona - European Society of Human Genetics

Molecular and biochemical basis of disease
P06.156
increasing power of variance component linkage analysis of
large pedigrees
T. I. Axenovich, I. V. Zorkoltseva, G. R. Svischeva;
Institute of Cytology and Genetics, Novosibirsk, Russian Federation.
Most methods of linkage analysis of quantitative traits are based on
the variance component approach . IBD calculation is the most computationally
intensive step of this approach . The size of IBD matrix for
large pedigrees and especially for those coming from isolated populations
is too large for practical calculation . To solve this problem a
pedigree is split on smaller non-overlapping fragments and then the
fragments are analyzed as independent pedigrees . The split leads to
increase the number of IBD matrix elements with zero values . This in
turn decreases the linkage power . To diminish this effect we suggested
to increase the number of non zero elements of IBD matrix by additional
alternative splitting of the pedigree, for example, on overlapping
fragments . Using the pedigree with 207 members in 6 generations, we
estimated the expected linkage power when IBDs were calculated for
a) pairs of genotyped members of each non-overlapping fragments of
size no more than 18 bit and b) for (a) plus additional pairs of genotyped
relatives from overlapping fragments of size no more than 18 bit .
The results demonstrated the effectiveness of our method: the power
for variant (b) based on 964 IBDs was 1 .2 - 1 .7 times greater than for
variant (a) based on 844 IBDs . Such once calculated IBD matrix can
further be utilized by various programs (for example, SOLAR) for linkage
analysis of different traits .
P06.157
A genome-wide association analysis of HDL-cholesterol in the
population-based KORA study sheds new light on intergenic
regions
I. M. Heid 1,2 , E. Boes 3 , M. Mueller 1,2 , B. Kollerits 3 , C. Lamina 1 , S. Coassin 3 , C.
Gieger 1,2 , A. Doering 1 , N. Klopp 1 , R. Frikke-Schmidt 4 , A. Tybjærg-Hansen 4 , A.
Brandstätter 3 , T. Meitinger 1 , H. Wichmann 1,2 , F. Kronenberg 3 ;
1 Helmholtz Zentrum München, Neuherberg, Germany, 2 Ludwig-Maximilians-
University of Munich, Munich, Germany, 3 Innsbruck Medical University, Innsbruck,
Austria, 4 Copenhagen University Hospital, Copenhagen, Denmark.
Objective: High-density lipoprotein cholesterol (HDLC) is a strong
risk factor for atherosclerosis and assumed to be under considerable
genetic control. We aimed to identify gene regions influencing HDLC
levels by a genome-wide association (GWA) analysis in the population-based
KORA Study .
Methods: In KORA S3/F3 (n=1,643), we analyzed the 377,865 qualitychecked
single nucleotide polymorphisms (SNPs) of the 500K Affymetrix
SNP array, complemented by the publicly available GWA results
from the Diabetes Genetics Initiative (DGI, n=2,631) and by replication
studies in KORA S4 (n=4,037) and the Copenhagen City Heart Study
(n=9,205) .
Results: Among the 13 SNPs selected from the KORA S3/F3 500K pvalue
list, three SNPs showed consistent associations in subsequent
replications: two from so far unreported regions 50 kb downstream of
LIPG or upstream of CETP and one from already reported regions of
the LPL . The SNP in CETP and several SNPs downstream of LIPG
were independent from already reported SNPs and might be of functional
relevance . The other 10 as well as further 13 SNPs selected
from the combined GWA p-value list of KORA S3/F3 and DGI failed
consistent replication .
Conclusions: Our GWA study identified two new HDLC-relevant regions,
which generally motivates to extend the focus of future genetic
association studies on long-range effects of intergenic regions . Furthermore,
our study reinforced CETP and LPL as strong HDLC genes
and thereby underscores the power of our study and of the GWA approach
in general to pinpoint strong effects from common polymorphisms
.
P06.158
Genetic variants in the UsF1 gene are not associated with mets,
T2DM, and related parameters in Caucasians (KORA study)
N. Klopp 1 , C. Holzapfel 1 , H. Grallert 1 , C. Huth 1 , C. Gieger 1 , C. Meisinger 1 , K.
Strassburger 2 , G. Giani 2 , H. Wichmann 1 , C. Herder 2 , W. Rathmann 2 , T. Illig 1 ;
1 Helmholtz Zentrum München, Munich-Neuherberg, Germany, 2 German Diabe-
tes Center, Leibniz Institute at Heinrich-Heine-University, Düsseldorf, Germany.
Upstream stimulatory factor 1 (USF1) regulates numerous genes of
glucose and lipid metabolism and genetic variants in the USF1 gene
show association with familial combined hyperlipidemia, which shows
phenotypic overlap with the metabolic syndrome (MetS) and type 2
diabetes mellitus (T2DM) . The aim of our study was to approve the
hypothesis that polymorphisms in the USF1 gene are associated with
MetS and related metabolic traits . We genotyped eight single nucleotide
polymorphisms in the USF1 gene in 1,653 individuals of the
population-based German Caucasian KORA study in the age range
between 55 and 74 years . Because of high correlation only six polymorphisms
were statistically analyzed . The association with T2DM and
the MetS was analyzed by logistic regression in 1,462 subjects and the
quantitative parameters were analyzed in 1,231 fasting non diabetic
subjects by linear regression respectively by Kruskal-Wallis test . None
of the analyzed genetic variants (rs2774279, rs10908821, rs1556259,
rs2516839, rs3737787, rs2774276) show significant association with
T2DM and MetS . The results for the metabolic traits like triglycerides,
total cholesterol, HDL cholesterol, LDL cholesterol, percent body fat,
waist to hip ratio, ureic acid, fasting glucose, 2 hour plasma glucose,
fasting insulin, blood pressure give also no evidence for any association
with USF1 . In our large population based study no association between
single genetic variants in the USF1 gene and T2DM, MetS and
related metabolic parameters was found . We conclude that the single
genetic variants in USF1 have no major effect on lipid and glucose
parameters in German Caucasians .
P06.159
Genome-wide linkage analysis for identifying quantitative trait
loci involved in the regulation of lipoprotein a (lpa) levels
S. Lopez 1 , A. Buil 1,2 , J. Ordoñez 3,4 , J. C. Souto 1 , L. Almasy 5 , M. Lathrop 6 , J.
Blangero 5 , F. Blanco-Vaca 3,7 , J. Fontcuberta 1 , J. M. Soria 1,2 ;
1 Haemostasis and Thrombosis Unit, Department of Hematology, Hospital de la
Santa Creu i Sant Pau, Barcelona, Spain, 2 Bioinformatic of Complex Diseases
Unit. Research Institute of Hospital de la Santa Creu i Sant Pau, Barcelona,
Spain, 3 Department of Biochemistry. Hospital de la Santa Creu i Sant Pau, Barcelona,
Spain, 4 Department of Biochemistry and Molecular Biology. Universitat
Autònoma de Barcelona, Barcelona, Spain, 5 Department of Population Genetics.
Southwest Foundation for Biomedical Research, San Antonio, TX, United
States, 6 Centre National du Genotypage, Paris, France, 7 CIBER de Diabetes y
Enfermedades Metabólicas Asociadas, Barcelona, Spain.
Lipoprotein Lp(a) levels are highly heritable and are associated with
cardiovascular risk . We performed a genome-wide linkage analysis
to delineate the genomic regions that influence the concentration of
Lp(a) in families from the Genetic Analysis of Idiopathic Thrombophilia
(GAIT) Project . Lp(a) levels were measured in 387 individuals belonging
to 21 extended Spanish families . A total of 485 DNA microsatellite
markers were genotyped to provide a 7 .1 cM genetic map . A variance
component linkage method was used to evaluate linkage and to detect
quantitative trait loci (QTLs) . The main QTL that showed strong evidence
of linkage with Lp(a) levels was located at the structural gene
for apo(a) on Chromosome 6 (LOD score=13 .8) . Interestingly, another
QTL influencing Lp(a) concentration was located on Chromosome
2 with a LOD score of 2 .01 . This region contains several candidate
genes . One of them is the tissue factor pathway inhibitor (TFPI), which
has antithrombotic action and also has the ability to bind lipoproteins .
However, quantitative trait association analyses performed with 12
SNPs in TFPI gene revealed no association with Lp(a) levels . Our
study confirms previous results on the genetic basis of Lp(a) levels.
In addition, we report a new QTL on Chromosome 2 involved in the
quantitative variation of Lp(a) . These data should serve as the basis
for further detection of candidate genes and to elucidate the relationship
between the concentration of Lp(a) and cardiovascular risk .
P06.160
Identification of a novel autosomal recessive locus on
chromosome 5q31-34 for the long Qt syndrome
Z. N. Al-Hassnan, S. Majid, M. Al-Fayyadh, N. Dzimiri, Y. Mallawi, W. Al Manea,
M. Al-Owain, B. Meyer;
King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.
It is estimated that a significant percentage of sudden deaths are due
to the long QT syndrome (LQTS) which is an inherited arrhythmogenic
disorder that is characterized by locus heterogeneity . Mutations in