We conducted a genome-wide association meta-analysis of 4,604 endometriosis cases and 9,393 controls of Japanese1 and European2 ancestry. We show that rs12700667 on chromosome 7p15.2, previously found to associate with disease in Europeans, replicates in Japanese (P = 3.6 × 10−3), and we confirm association of rs7521902 at 1p36.12 near WNT4. In addition, we establish an association of rs13394619 in GREB1 at 2p25.1 with endometriosis and identify a newly associated locus at 12q22 near VEZT (rs10859871). Excluding cases of European ancestry of minimal or unknown severity, we identified additional previously unknown loci at 2p14 (rs4141819), 6p22.3 (rs7739264) and 9p21.3 (rs1537377). All seven SNP effects were replicated in an independent cohort and associated at P <5 × 10−8 in a combined analysis. Finally, we found a significant overlap in polygenic risk for endometriosis between the genome-wide association cohorts of European and Japanese descent (P = 8.8 × 10−11), indicating that many weakly associated SNPs represent true endometriosis risk loci and that risk prediction and future targeted disease therapy may be transferred across these populations.

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  1. 1.

    et al. A genome-wide association study identifies genetic variants in the CDKN2BAS locus associated with endometriosis in Japanese. Nat. Genet. 42, 707–710 (2010).

  2. 2.

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

  3. 3.

    , , & Genetic influences on endometriosis in an Australian twin sample. Fertil. Steril. 71, 701–710 (1999).

  4. 4.

    et al. The search for genes contributing to endometriosis risk. Hum. Reprod. Update 14, 447–457 (2008).

  5. 5.

    et al. Economic burden of endometriosis. Fertil. Steril. 86, 1561–1572 (2006).

  6. 6.

    , , & Five years of GWAS discovery. Am. J. Hum. Genet. 90, 7–24 (2012).

  7. 7.

    et al. Cohort profile: The Hunter Community Study. Int. J. Epidemiol. 39, 1452–1463 (2010).

  8. 8.

    American Society for Reproductive Medicine. Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil. Steril. 67, 817–821 (1997).

  9. 9.

    et al. Meta-analysis of genome-wide association scans for genetic susceptibility to endometriosis in Japanese population. J. Hum. Genet. 55, 816–821 (2010).

  10. 10.

    , , , & Loss of heterozygosity in adenomyosis on hMSH2, hMLH1, p16Ink4 and GALT loci. Int. J. Mol. Med. 6, 667–671 (2000).

  11. 11.

    et al. Possible involvement of hMLH1, p16INK4a and PTEN in the malignant transformation of endometriosis. Int. J. Cancer 102, 398–406 (2002).

  12. 12.

    et al. Genomic inflation factors under polygenic inheritance. Eur. J. Hum. Genet. 19, 807–812 (2011).

  13. 13.

    et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460, 748–752 (2009).

  14. 14.

    et al. A versatile gene-based test for genome-wide association studies. Am. J. Hum. Genet. 87, 139–145 (2010).

  15. 15.

    , , , & Female development in mammals is regulated by Wnt-4 signalling. Nature 397, 405–409 (1999).

  16. 16.

    et al. Down-regulation of VEZT gene expression in human gastric cancer involves promoter methylation and miR-43c. Biochem. Biophys. Res. Commun. 404, 622–627 (2011).

  17. 17.

    et al. WNT4 is required for normal ovarian follicle development and female fertility. FASEB J. 24, 3010–3025 (2010).

  18. 18.

    et al. GREB 1 is a critical regulator of hormone dependent breast cancer growth. Breast Cancer Res. Treat. 92, 141–149 (2005).

  19. 19.

    et al. Genomewide linkage study in 1,176 affected sister pair families identifies a significant susceptibility locus for endometriosis on chromosome 10q26. Am. J. Hum. Genet. 77, 365–376 (2005).

  20. 20.

    et al. Common variants in the trichohyalin gene are associated with straight hair in Europeans. Am. J. Hum. Genet. 85, 750–755 (2009).

  21. 21.

    , & Population structure and eigenanalysis. PLoS Genet. 2, e190 (2006).

  22. 22.

    et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).

  23. 23.

    et al. PLINK: a tool set for whole-genome association and population-based linkage analysis. Am. J. Hum. Genet. 81, 559–575 (2007).

  24. 24.

    & GWAMA: software for genome-wide association meta-analysis. BMC Bioinformatics 11, 288 (2010).

  25. 25.

    et al. MGEx-Udb: a mammalian uterus database for expression-based cataloguing of genes across conditions, including endometriosis and cervical cancer. PLoS ONE 7, e36776 (2012).

  26. 26.

    & Estimation of significance thresholds for genomewide association scans. Genet. Epidemiol. 32, 227–234 (2008).

  27. 27.

    The combination of estimates from different experiments. Biometrics 10, 101–129 (1954).

  28. 28.

    , & Heterogeneity in meta-analyses of genome-wide association investigations. PLoS ONE 2, e841 (2007).

  29. 29.

    & Random-effects model aimed at discovering associations in meta-analysis of genome-wide association studies. Am. J. Hum. Genet. 88, 586–598 (2011).

  30. 30.

    & Meta-analysis in clinical trials. Control. Clin. Trials 7, 177–188 (1986).

  31. 31.

    , , & Genotype imputation. Annu. Rev. Genomics Hum. Genet. 10, 387–406 (2009).

  32. 32.

    , , , & MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet. Epidemiol. 34, 816–834 (2010).

  33. 33.

    , & METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26, 2190–2191 (2010).

  34. 34.

    , , , & Adjustment During Army Life. (Princeton University Press, Princeton, NJ, 1949).

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We acknowledge with appreciation all the women who participated in the QIMR, OX and BBJ studies. We thank Endometriosis Associations for supporting 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 Sullivan and Nicolaides Pathology and the Queensland Medical Laboratory Pathology for pro bono collection and delivery of blood samples and other pathology services for assistance with blood collection. The HCS team thanks the men and women of the Hunter region who participated in the study.

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 disease stage 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 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 Australian Research Council (ARC) Future Fellowship (FT0991022) schemes. S.M. was supported by NHMRC Career Development Awards (496674 and 613705). E.G.H. (631096) and G.W.M. (339446 and 619667) were supported by the NHMRC Fellowship scheme. The HCS was funded by the University of Newcastle, the Gladys M Brawn Fellowship scheme and the Vincent Fairfax Family Foundation in Australia.

We thank L. Cotton, L. Pope, G. Chalk and G. Farmer. We also thank P. Koninckx, M. Sillem, C. O'Herlihy, M. Wingfield, M. Moen, L. Adamyan, E. McVeigh, C. Sutton, D. Adamson and R. Batt for providing diagnostic confirmation. The work presented here was supported by a grant from the Wellcome Trust (WT084766/Z/08/Z) and makes use of Wellcome Trust Case Control Consortium 2 (WTCCC2) control data generated by the WTCCC. A full list of the investigators who contributed to the generation of these data is available at the Wellcome Trust website (see URLs). Funding for the WTCCC project was provided by the Wellcome Trust under awards 076113 and 085475. C.A.A. was supported by a grant from the Wellcome Trust (098051). 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 National Institute for Health Research (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 the members of the Rotary Club of Osaka-Midosuji District 2660 Rotary International in Japan for supporting our study. This work was conducted as part of the BioBank Japan Project that was supported by the Ministry of Education, Culture, Sports, Science and Technology of the Japanese government.

Author information

Author notes

    • Dale R Nyholt
    •  & Siew-Kee Low

    These authors contributed equally to this work.

    • Krina T Zondervan
    • , Hitoshi Zembutsu
    •  & Grant W Montgomery

    These authors jointly directed this work.


  1. Queensland Institute of Medical Research, Brisbane, Queensland, Australia.

    • Dale R Nyholt
    • , Jodie N Painter
    • , Stuart MacGregor
    • , Scott D Gordon
    • , Anjali K Henders
    • , Nicholas G Martin
    •  & Grant W Montgomery
  2. Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.

    • Siew-Kee Low
    • , Satoko Uno
    • , Yusuke Nakamura
    •  & Hitoshi Zembutsu
  3. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.

    • Carl A Anderson
  4. First Department of Surgery, Sapporo Medical University, School of Medicine, Sapporo, Japan.

    • Satoko Uno
  5. Genetic and Genomic Epidemiology Unit, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Andrew P Morris
    •  & Krina T Zondervan
  6. Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia.

    • John Attia
    • , Elizabeth G Holliday
    •  & Mark McEvoy
  7. Centre for Bioinformatics, Biomarker Discovery and Information-Based Medicine, Hunter Medical Research Institute, Newcastle, New South Wales, Australia.

    • John Attia
    • , Elizabeth G Holliday
    •  & Rodney J Scott
  8. School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia.

    • Mark McEvoy
  9. Public Health Research Program, Hunter Medical Research Institute, Newcastle, New South Wales, Australia.

    • Mark McEvoy
  10. School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia.

    • Rodney J Scott
  11. Division of Genetics, Hunter Area Pathology Service, Newcastle, New South Wales, Australia.

    • Rodney J Scott
  12. Nuffield Department of Obstetrics and Gynaecology, University of Oxford, John Radcliffe Hospital, Oxford, UK.

    • Stephen H Kennedy
    •  & Krina T Zondervan
  13. Centre for Military and Veterans' Health, University of Queensland, Mayne Medical School, Brisbane, Queensland, Australia.

    • Susan A Treloar
  14. Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Stacey A Missmer
  15. Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

    • Sosuke Adachi
    •  & Kenichi Tanaka


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Manuscript preparation and final approval: D.R.N., S.-K.L., C.A.A., J.N.P., S.U., A.P.M., S.M., S.D.G., A.K.H., N.G.M., J.A., E.G.H., M.M., R.J.S., S.H.K., S.A.T., S.A.M., S.A., K.T., Y.N., K.T.Z., H.Z. and G.W.M. Study conception and design: D.R.N., S.M., Y.N., K.T.Z., H.Z. and G.W.M. GWAS data collection, sample preparation and clinical phenotyping: J.N.P., S.U., A.K.H., N.G.M., J.A., E.G.H., M.M., R.J.S., S.H.K., S.A.T., K.T.Z., H.Z. and G.W.M. Replication data collection, sample preparation and clinical phenotyping: S.A., K.T. and H.Z. Replication genotyping: H.Z. Data analysis: genome-wide association analysis: D.R.N., C.A.A. and S.-K.L.; imputation and replication analysis: D.R.N. and S.-K.L.; polygenic prediction, gene-based analysis and meta-analysis: D.R.N. Obtaining study funding: D.R.N., S.M., N.G.M., S.H.K., S.A.T., S.A.M., Y.N., K.T.Z. and G.W.M.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Dale R Nyholt or Krina T Zondervan or Hitoshi Zembutsu or Grant W Montgomery.

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