Mol. Hum. Reprod. Advance Access published online on June 29, 2006
Molecular Human Reproduction, doi:10.1093/molehr/gal056
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1 Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, TX, USA
* To whom correspondence should be addressed. Pre-eclampsia/eclampsia (PE/E) is a common, serious medical disorder of human pregnancy. Familial association of PE/E has been recognized for decades, but the genetics are complex and poorly understood. In an attempt to identify PE/E susceptibility genes, we embarked on a positional cloning strategy using 34 Australian and New Zealand PE/E pedigrees. An initial 10-cM resolution genome scan revealed a putative susceptibility locus spanning a broad region on chromosome 2 that overlaps an independently determined linkage signal seen in Icelandic PE pedigrees. Subsequent fine mapping using 25 additional short tandem repeat (STR) markers in this region and non-parametric multipoint linkage analysis did not change the overall position. Under a strict diagnosis of PE, we obtained significant evidence of linkage on 2q with a peak log-of-odds ratio score (LOD) of 3.43 near marker D2S151 at 155 cM. To prioritize positional candidate genes at the 2q locus for detailed analysis, we applied an objective prioritiza-tion strategy that integrates quantitative bioinformatics, assessment of differential gene expression and association analysis of single-nucleotide polymorphisms (SNPs). Highest priority was assigned to the activin receptor gene ACVR2. This gene also showed >10-fold differential gene expression in human decidual tissue from normotensive and PE individuals. We genotyped five known SNPs in this gene in our pedigrees and performed tests for association and linkage disequilibrium. One SNP (rs1424954) showed strong preliminary evidence of association with PE (P = 0.007), whereas two others (rs1364658 and rs1895694) exhibited nominal evidence (P < 0.05). Haplotype analysis revealed no additional association information. There was evidence of weak linkage disequilibrium among these SNPs. The highest observed LD occurred between the two strongest associated SNPs, suggesting that the observed signals may be the signature of an observed functional variant.
Received April 14, 2006
Revised May 17, 2006
Accepted May 23, 2006
Article
Objective prioritization of positional candidate genes at a quantitative trait locus for pre-eclampsia on 2q22
E.K. Moses 1 *,
E. Fitzpatrick 2,
K.A. Freed 2,
T.D. Dyer 1,
S. Forrest 3,
K. Elliott 4,
M.P. Johnson 1,
J. Blangero 1,
and
S.P. Brennecke 2
2 Department of Perinatal Medicine and the University of Melbourne Department of Obstetrics & Gynaecology, Royal Women’s Hospital, Carlton
3 Australian Genome Research Facility Ltd, Parkville
4 ChemGenex Pharmaceuticals, Geelong, Victoria, Australia; Present address: Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK
E.K. Moses, E-mail: moses{at}darwin.sfbr.org
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