Genome-wide association study of endometriosis identifies a locus at 7p15.2 with pleiotropic effects
K. Zondervan1, J. Painter2, N. Rahmioglu1, D. Nyholt2, C. Anderson3, S. MacGregor2, H. Lee2, P. Visscher2, P. Kraft4, N. Martin2, A. Morris1, S. Treloar3, S. Kennedy2, C. Lindgren1, S. Missmer4,5 & G. Montgomery3
Endometriosis is a common gynaecological disease associated with severe pelvic pain and sub-fertility. We conducted a genome-wide association (GWA) study in 3,194 surgically confirmed endometriosis cases and 7060 controls of European ancestry from Australia and the UK using 540,000 genetic markers (SNPs). Polygenic predictive modelling showed significantly increased genetic loading among the 1364 (43%) cases with moderate-severe (rAFS III/IV) endometriosis. The strongest association signal was observed on chromosome 7p15.2 for SNP rs12700667 for all endometriosis (P=2.6×10−7, OR=1.22 (1.131.32)) and for moderate-severe disease, (P=1.5×10−9 (OR=1.38 (1.241.53)). We replicated rs12700667 in an independent US cohort of 2392 self-reported surgically confirmed endometriosis cases and 2271 controls (P=1.2× 10−3, OR=1.17 (1.061.28)), resulting in a genome-wide significant P value of 1.4×10−9 (OR=1.20 (1.131.27)) for all endometriosis in our combined datasets.
Rs12700667 is located in a 48 kb genomic segment of high LD, and marked one of 13 loci associated with waist-hip ratio adjusted for BMI (WHRadjBMI) in an independent GWA dataset of 77,167 individuals using ~2.8 million genotyped and imputed SNPs (top SNP rs1055144: P=1.49×10−8). P-values for 5/12 other WHRadjBMI-associated SNPs varied from 0.01 to 0.81 for all endometriosis and from 0.05 to 0.77 for rAFS III/IV cases. The probability of finding a common genetic locus associated with two traits by chance at the given significance levels was, allowing for multiple testing of 6 SNPs, very small: P=2.2×10−4. Alleles of SNPs at 7p15.2 which are associated with increased risk of moderate-severe endometriosis are associated with decreased WHRadjBMI (pear-shape), consistent with hypotheses of hormonal regulation for both, suggesting that the locus has pleiotropic effects on the two phenotypes. Further results will be discussed.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This work was supported, however funding details are unavailable.