2008 Barcelona - European Society of Human Genetics

Molecular and biochemical basis of disease
found between T1D patients and controls . The 1858T allele presented
an association with both T1D (OR=1 .73, 95%CI 1 .19-2 .51, p=0 .0035)
and AAD (OR=1 .84, 95%CI 1 .15-2 .94, p=0 .0099) . 1858T was associated
with both diseases in males (p=0 .022 and p=0 .008, respectively) .
No statistical difference in females was found. Stratification according
to the presence of concomitant autoimmune disorders revealed an association
of 1858T with both clinical forms of T1D and polyendocrine
cases of AAD . G(-1123)C and C1858T were in linkage disequilibrium
(D’=1 .000; r 2 =0 .5396 for AAD, and D’=0 .9818; r 2 =0 .6104 in T1D) . No
significant association between the PTPN22 haplotypes and ADD was
found. The haplotype including both mutant alleles was significantly
more frequent in T1D than in controls (p=0.0033). The results confirm
the association of PTPN22 C1858T polymorphism with T1D and AAD
in Polish male population, while the G(-1123)C impact is less explicit .
P06.248
mutation analysis of the PVRL1 gene in caucasians with nonsyndromic
cleft lip/palate
M. A. Sözen 1,2 , R. A. Spritz 2 ;
1 Afyon Kocatepe University School of Medicine, Afyonkarahisar, Turkey, 2 University
of Colorado Denver Anschutz Medical Campus, Aurora, CO, United
States.
Non-syndromic cleft lip with or without cleft palate (CL/P, MIM 119530)
is perhaps one of the most common major birth defects . It has been
shown that homozygosity for a nonsense mutation of PVRL1, W185X,
result in an autosomal recessive CL/P syndrome (CLPED1), whereas
heterozygosity for the same mutation is associated with sporadic, nonsyndromic
CL/P in Venezuela . The aim of the study was to investigate
further involvement of the PVRL1 gene in non-syndromic cleft lip and/
or palate in North American and Australian Caucassian populations .
Therefore, a mutation analysis of PVRL1 gene covering all isoforms
were carried out in 216 North American and Australian Caucasian
patients and 223 population-matched controls using Single Stranded
both populations studied . Particularly two variants were more frequent
in Caucasian nsCL/P patients than in Caucasian controls . One, an inframe
insertion at Glu442, was more frequent in Caucasian nsCL/P
patients than in Caucasian controls though not significant and another,
S447L (PVRL1 beta isoform specific one), was found to be significantly
more frequent in non-syndromic CL/P in North American Caucasian
patients versus controls (p= .032), despite its failure to replicate in Australian
population . These results suggest that PVRL1 may play a minor
role in susceptibility to the occurrence of nsCL/P in Caucasian populations
. It also suggests that the beta (HIgR) isoform might have a particular
importance for craniofacial development based on this marginal
association, and suggesting a possible genetic heterogeneity in the
development of non-syndromic CL/P among the populations studied .
P06.249
Detecting associations in the presence of extreme allelic
heterogeneity: Application to the rare variant common disease
hypothesis
B. Li, S. M. Leal;
Baylor College of Medicine, Houston, TX, United States.
Association studies are frequently utilized to map variants which are
susceptibility loci for common diseases . Critical assumptions of this
approach are that the disease is due to a common functional variant
which is in strong linkage disequilibrium with genotyped SNP(s)
and there is minimal allelic heterogeneity . If the rare variant common
disease hypothesis holds, current association based methods will be
underpowered due to allelic heterogeneity, low allele frequencies and
poor correlation (r 2 ) with tagSNPs . For common diseases where the
underlying etiology is believed to involve extreme allelic heterogeneity,
large scale candidate gene sequencing is currently underway to
discover multiple causal rare variants . However, which methods are
optimal for analyzing this type of data to detect associations is unknown
. In this study, we analytically demonstrate that collapsing genotypes
and rare variants across multiple loci is more powerful than
multi-marker test (Hotelling’s T 2 ) and single marker test (Fisher exact
test) . Although bioinformatics tools are used to classify variants, variants
can be misclassified and erroneously included or excluded from
the analysis based upon predicted functionality . Collapsing methods
are robust against misclassification of rare variants, but misclassification
of common variants can lead to a substantial loss of power . For
the situation where it is suspected that both common and rare variants
are involved in disease etiology a powerful and robust novel method
was developed which combines collapsing and multilocus tests . It is
also demonstrated empirically that for both collapsing and combined
methods type I error is well controlled .
P06.250
New mutation in the iGF-i receptor (iGF1R) gene associated with
intrauterine growth retardation
E. Barrio 1 , M. CALVO 1 , J. Labarta 2 , M. Miramar 1 , F. Lorente 1 , A. Rodriguez 1 , E.
Mayayo 2 , A. Ferrández Longás 2 ;
1 Molecular Genetics, HMI Miguel Servet, University of Zaragoza, ZARAGOZA,
Spain, 2 Unit of Pediatric Endocrinology, HMI Miguel Servet, University of Zaragoza,
ZARAGOZA, Spain.
PATIENTS: We have studied 55 spanish patients with short stature
(