Hum. Reprod. Advance Access originally published online on December 11, 2006
Human Reproduction 2007 22(3):717-728; doi:10.1093/humrep/del446
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Significant evidence of one or more susceptibility loci for endometriosis with near-Mendelian inheritance on chromosome 7p13–15
1 Wellcome Trust Centre for Human Genetics 2 Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford, UK 3 Cooperative Research Centre for Discovery of Genes for Common Human Diseases, Melbourne 4 Queensland Institute of Medical Research, Brisbane, Australia 5 College of Life Sciences, Sun Yat-sen University, Guangzhou, China 6 Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, UK 7 Oxagen, Abingdon, UK 8 Study Group: Queensland Institute of Medical Research, Brisbane, Australia: Jacqueline Wicks, Brandon J.Wainwright, and Anjali Henders; Oxagen, Abingdon, UK: Delilah Zabaneh, Gary Dawson, Vicki Smith, Alisoun Carey, and Simon T.Bennett; Queensland Endometriosis Research Institute, Brisbane, Australia: Daniel T.O'Connor; Nuffield Department of Obstetrics and Gynaecology, University of Oxford, UK: David Barlow, and Ann Lambert; Australian Genome Research Facility, Melbourne, Australia: Kelly R.Ewen-White
9 To whom correspondence should be addressed at: E-mail: krinaz{at}well.ox.ac.uk
BACKGROUND: Endometriosis is a common disease with a heritable component. The collaborative International Endogene Study consists of two data sets (Oxford and Australia) comprising 1176 families with multiple affecteds. The aim was to investigate whether the apparent concentration of cases in a proportion of families could be explained by one or more rare variants with (near-)Mendelian autosomal inheritance.
METHODS AND RESULTS: Linkage analyses (aimed at finding chromosomal regions harbouring disease-predisposing genes) were conducted in families with three or more affected (Oxford: n = 52; Australia: n = 196). In the Oxford data set, a non-parametric linkage score (Kong & Cox (K&C) Log of ODds (LOD)) of 3.52 was observed on chromosome 7p (genome-wide significance P = 0.011). A parametric MOD score (equal to maximum LOD maximized over 357 possible inheritance models) of 3.89 was found at 65.72 cM (D7S510) for a dominant model with reduced penetrance. After including the Australian data set, the non-parametric K&C LOD of the combined data set was 1.46 at 57.3 cM; the parametric analysis found an MOD score of 3.30 at D7S484 (empirical significance: P = 0.035) for a recessive model with high penetrance. Critical recombinant analysis narrowed the probable region of linkage down to overlapping 6.4 Mb and 11 Mb intervals containing 48 and 96 genes, respectively.
CONCLUSIONS: This is the first report to suggest that there may be one or more high-penetrance susceptibility loci for endometriosis with (near-)Mendelian inheritance.
Key words: chromosome 7/endometriosis/family study/linkage
Submitted on July 21, 2006; resubmitted on September 6, 2006; accepted on September 19, 2006.
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