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Genome-wide association study identifies a locus at 7p15.2 associated with endometriosis


Endometriosis is a common gynecological disease associated with pelvic pain and subfertility. We conducted a genome-wide association study (GWAS) in 3,194 individuals with surgically confirmed endometriosis (cases) and 7,060 controls from Australia and the UK. Polygenic predictive modeling showed significantly increased genetic loading among 1,364 cases with moderate to severe endometriosis. The strongest association signal was on 7p15.2 (rs12700667) for 'all' endometriosis (P = 2.6 × 10−7, odds ratio (OR) = 1.22, 95% CI 1.13–1.32) and for moderate to severe disease (P = 1.5 × 10−9, OR = 1.38, 95% CI 1.24–1.53). We replicated rs12700667 in an independent cohort from the United States of 2,392 self-reported, surgically confirmed endometriosis cases and 2,271 controls (P = 1.2 × 10−3, OR = 1.17, 95% CI 1.06–1.28), resulting in a genome-wide significant P value of 1.4 × 10−9 (OR = 1.20, 95% CI 1.13–1.27) for 'all' endometriosis in our combined datasets of 5,586 cases and 9,331 controls. rs12700667 is located in an intergenic region upstream of the plausible candidate genes NFE2L3 and HOXA10.

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Figure 1: Allele-specific score prediction for endometriosis, using the Oxford population as the discovery dataset and the QIMR population as the target dataset.
Figure 2: Evidence for association with endometriosis across the chromosome 7 region following imputation using HapMap 3 and 1000 Genomes Project CEU and TSI reference panels.


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We acknowledge with appreciation all the women who participated in the QIMR, OXEGENE and NHS studies. We thank Endometriosis Associations for supporting the study recruitment. We also thank the many hospital directors and staff, gynecologists, general practitioners and pathology services in Australia, the UK and the United States who provided assistance with confirmation of diagnoses. We thank S. Nicolaides and the Queensland Medical Laboratory for pro bono collection and delivery of blood samples and other pathology services for assistance with blood collection.

The QIMR Study was supported by grants from the National Health and Medical Research Council (NHMRC) of Australia (241944, 339462, 389927, 389875, 389891, 389892, 389938, 443036, 442915, 442981, 496610, 496739, 552485 and 552498), the Cooperative Research Centre for Discovery of Genes for Common Human Diseases (CRC), Cerylid Biosciences (Melbourne) and donations from N. Hawkins and S. Hawkins. D.R.N. was supported by the NHMRC Fellowship (339462 and 613674) and the ARC Future Fellowship (FT0991022) schemes. S.M. was supported by NHMRC Career Development Awards (496674, 613705). P.M.V. (442915) and G.W.M. (339446, 619667) were supported by the NHMRC Fellowships Scheme. We thank B. Haddon, D. Smyth, H. Beeby, O. Zheng, B. Chapman and S. Medland for project and database management, sample processing, genotyping and imputation. We thank Brisbane gynecologist D.T. O'Connor for his important role in initiating the early stages of the project and for confirmation of diagnosis and staging of disease from clinical records of many cases, including 251 in these analyses. We are grateful to the many research assistants and interviewers for assistance with the studies contributing to the QIMR collection.

The work presented here was supported by a grant from the Wellcome Trust (WT084766/Z/08/Z) and makes use of WTCCC2 control data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of these data is available from Funding for the WTCCC project was provided by the Wellcome Trust under awards 076113 and 085475. Imputation analyses were conducted using computational resources at the Oxford Supercomputing Centre (OSC). C.A.A. was funded by the Wellcome Trust (WT91745/Z/10/Z). A.P.M. was supported by a Wellcome Trust Senior Research Fellowship. S.H.K. is supported by the Oxford Partnership Comprehensive Biomedical Research Centre with funding from the Department of Health NIHR Biomedical Research Centres funding scheme. K.T.Z. is supported by a Wellcome Trust Research Career Development Fellowship (WT085235/Z/08/Z). We thank L. Cotton, L. Pope, G. Chalk and G. Farmer (University of Oxford). We also thank P. Koninckx (Leuven, Belgium), M. Sillem (Heidelberg, Germany), C. O'Herlihy and M. Wingfield (Dublin, Ireland), M. Moen (Trondheim, Norway), L. Adamyan (Moscow, Russia), E. McVeigh (Oxford, UK), C. Sutton (Guildford, UK), D. Adamson (Palo Alto, California, USA) and R. Batt (Buffalo, New York, USA) for providing diagnostic confirmation.

The Nurse' Health Studies I and II were supported by grants from the National Institutes of Health (NIH) of the United States, NHS1 cohort (primary investigator: S. Hankinson)-P01 CA087969, NHS1 blood cohort (primary investigator, S. Hankinson)-R01 CA049449, NHS1 Breast Cancer GWAS (primary investigator, D. Hunter)-UO1 CA098233, NHS1/NHS2 Kidney Stones GWAS (primary investigator, G. Curhan)-P01 DK070756, NHS2 cohort (primary investigator, W. Willett)-R01 CA050385, NHS2 blood cohort (primary investigator, S. Hankinson)-R01 CA067262, NHS2 endometriosis (primary investigator, S. Missmer)-R01 HD052473 and R01 HD057210. We thank L. Marshall, D. Hunter and R. Barbieri for their contributions to the endometriosis case validation study and B. Egan and L. Ward for surgical records procurement.

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Authors and Affiliations



The International Endogene Consortium

Manuscript preparation: J.N.P., C.A.A., D.R.N., S.M., S.H.L., P.M.V., P.K., N.G.M., A.P.M., S.A.T., S.H.K., S.A.M., G.W.M., K.T.Z.

Study conception and design: J.N.P., C.A.A., D.R.N., P.M.V., N.G.M., S.M., A.P.M., S.A.T., S.H.K., S.A.M., G.W.M., K.T.Z.

GWAS data collection, sample preparation and clinical phenotyping: J.N.P., J.L., A.L., F.R., L.W., A.K.H., N.G.M., S.A.T., S.H.K., G.W.M., K.T.Z.

Replication datasets collection and clinical phenotyping: Q.G., P.K., S.A.M.

Replication genotyping: Z.Z.Z., A.K.H., G.W.M.

Data analysis: GWAS analysis subgroup: J.N.P., C.A.A., D.R.N., S.D.G., A.P.M., K.T.Z.; proportion of variance subgroup: S.H.L., P.M.V.; polygenic prediction analysis subgroup: S.M., P.M.V.; replication and meta-analysis subgroup: J.N.P., D.R.N., Q.G., P.K. S.A.M., G.W.M.; imputation: D.R.N., A.P.M.; bioinformatic analysis subgroup: J.N.P., G.W.M., K.T.Z.

Obtaining study funding: S.M., N.G.M., S.A.T., S.H.K., S.A.M., G.W.M., K.T.Z.

Corresponding authors

Correspondence to Jodie N Painter or Krina T Zondervan.

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The authors declare no competing financial interests.

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Painter, J., Anderson, C., Nyholt, D. et al. Genome-wide association study identifies a locus at 7p15.2 associated with endometriosis. Nat Genet 43, 51–54 (2011).

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