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

Jodie N Painter, Carl A Anderson, Dale R Nyholt, Stuart Macgregor, Jianghai Lin, Sang Hong Lee, Sang Lee, Ann Lambert, Zhen Z Zhao, Zhen Zhao, Fenella Roseman, Qun Guo, Scott D Gordon, Leanne Wallace, Anjali K Henders, Peter M Visscher, Peter Kraft, Nicholas G Martin, Andrew P Morris, Susan A Treloar, Stephen H Kennedy, Stephen Kennedy, Stacey A Missmer, Grant W Montgomery, Krina T Zondervan
Nature genetics · 2010 · vol. 43(1) , pp. 51–54 · doi:10.1038/ng.731 · PMID:21151130 · W2004442355
article OA: green CC0 ⤵ 188 in-corpus citations
🔓 Open OA copy Full text JSON View on OpenAlex View on PubMed View at publisher
⚙ AI-generated summary by claude@2026-06+body, 2026-06-07 ⓘ

A genome-wide association study identified a novel locus at 7p15.2, specifically rs12700667, significantly associated with endometriosis risk in combined Australian, UK, and US cohorts.

One-sentence paraphrase of the abstract; not a substitute for reading it. No clinical advice. How this works

⚙ AI-generated deep summary by claude@2026-06, 2026-06-07 · read from full text ⓘ

This genome-wide association study analyzed genetic variants in 3,194 individuals with surgically confirmed endometriosis from Australia/UK and 7,060 controls, with replication in an independent US cohort of 2,392 surgically confirmed cases and 2,271 controls. Using polygenic predictive modeling, the authors found increased genetic loading among cases with moderate-to-severe endometriosis, and the strongest association signal mapped to an intergenic locus at 7p15.2 (rs12700667), with genome-wide significant results for all endometriosis and for moderate-to-severe disease. Replication and meta-analysis supported the association (combined ORs around 1.20), and the locus is located upstream of plausible candidate genes NFE2L3 and HOXA10. The paper’s main limitation is that the locus-level signal does not identify the causal variant or mechanism within the intergenic region. This paper is centrally about endometriosis — it reports a GWAS locus at 7p15.2 associated with endometriosis risk and severity.

Read from the paper's body, not the abstract. Not a substitute for reading the paper. No clinical advice. How this works

Full text 15,299 characters · extracted from oa-doi-fallback · 3 sections · click to expand

Abstract

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. This is a preview of subscription content, access via your institution Access options Subscribe to this journal Receive 12 print issues and online access 251,40 € per year only 20,95 € per issue Buy this article - Purchase on SpringerLink - Instant access to the full article PDF. 39,95 € Prices may be subject to local taxes which are calculated during checkout Similar content being viewed by others

References

Giudice, L.C. & Kao, L.C. Endometriosis. Lancet 364, 1789–1799 (2004). Simoens, S., Hummelshoj, L. & D'Hooghe, T. Endometriosis: cost estimates and methodological perspective. Hum. Reprod. Update 13, 395–404 (2007). Jones, G.L., Kennedy, S.H. & Jenkinson, C. Health-related quality of life measurement in women with common benign gynecologic conditions: a systematic review. Am. J. Obstet. Gynecol. 187, 501–511 (2002). Kjerulff, K.H., Erickson, B.A. & Langenberg, P.W. Chronic gynecological conditions reported by US women: findings from the National Health Interview Survey, 1984 to 1992. Am. J. Public Health 86, 195–199 (1996). Anonymous. Revised American Fertility Society classification of endometriosis: 1985. Fertil. Steril. 43, 351–352 (1985). Koninckx, P.R., Oosterlynck, D., D'Hooghe, T. & Meuleman, C. Deeply infiltrating tendometriosis is a disease whereas mild endometriosis could be considered a non-disease. Ann. NY Acad. Sci. 734, 333–341 (1994). Hadfield, R.M., Mardon, H.J., Barlow, D.H. & Kennedy, S.H. Endometriosis in monozygotic twins. Fertil. Steril. 68, 941–942 (1997). Kennedy, S. The genetics of endometriosis. J. Reprod. Med. 43, 263–268 (1998). Treloar, S.A., O'Connor, D.T., O'Connor, V.M. & Martin, N.G. Genetic influences on endometriosis in an Australian twin sample. Fertil. Steril. 71, 701–710 (1999). Zondervan, K.T., Cardon, L.R. & Kennedy, S.H. The genetic basis of endometriosis. Curr. Opin. Obstet. Gynecol. 13, 309–314 (2001). Simpson, J.L. & Bischoff, F.Z. Heritability and molecular genetic studies of endometriosis. Ann. NY Acad. Sci. 955, 239–251 (2002). Stefansson, H. et al. Genetic factors contribute to the risk of developing endometriosis. Hum. Reprod. 17, 555–559 (2002). Zondervan, K.T. et al. Familial aggregation of endometriosis in a large pedigree of rhesus macaques. Hum. Reprod. 19, 448–455 (2004). Montgomery, G.W.M. et al. The search for genes contributing to endometriosis risk. Hum. Reprod. Update 14, 447–457 (2008). Treloar, S. et al. The International Endogene Study: a collection of families for genetic research in endometriosis. Fertil. Steril. 78, 679–685 (2002). Sturm, R.A. et al. A single SNP in an evolutionary conserved region within intron 86 of the HERC2 gene determines human blue-brown eye color. Am. J. Hum. Genet. 82, 424–431 (2008). Ferreira, M.A. et al. Quantitative trait loci for CD4:CD8 lymphocyte ratio are associated with risk of type 1 diabetes and HIV-1 immune control. Am. J. Hum. Genet. 86, 88–92 (2010). Yang, J. et al. Common SNPs explain a large proportion of heritability for human height. Nat. Genet. 42, 565–569 (2010). The International Schizophrenia Consortium et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460, 748–752 (2009). Hunter, D.J. et al. A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat. Genet. 39, 870–874 (2007). Missmer, S.A. et al. Incidence of laparoscopically confirmed endometriosis by demographic, anthropometric, and lifestyle factors. Am. J. Epidemiol. 160, 784–796 (2004). Kraft, P. Curses--winner?s and otherwise--in genetic epidemiology. Epidemiology 19, 649–651 (2008). Zondervan, K.T., Cardon, L.R. & Kennedy, S.H. What makes a good case-control study? Design issues for complex traits such as endometriosis. Hum. Reprod. 17, 1415–1423 (2002). Taylor, H.S., Bagot, C., Kardana, A., Olive, D. & Arici, A. HOX gene expression is altered in the endometrium of women with endometriosis. Hum. Reprod. 14, 1328–1331 (1999). Wu, Y. et al. Aberrant methylation at HOXA10 may be responsible for its aberrant expression in the endometrium of patients with endometriosis. Am. J. Obstet. Gynecol. 193, 371–380 (2005). Uno, S. 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). Vainio, S., Heikkilä, M., Kispert, A., Chin, N. & McMahon, A.P. Female development in mammals is regulated by Wnt-4 signalling. Nature 397, 405–409 (1999). Naillat, F. et al. Wnt4/5a signalling coordinates cell adhesion and entry into meiosis during presumptive ovarian follicle development. Hum. Mol. Genet. 19, 1539–1550 (2010). Boyer, A. et al. WNT4 is required for normal ovarian follicle development and female fertility. FASEB J. 24, 3010–3025 (2010). Treloar, S.A. 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). McGregor, B. et al. Genetic and environmental contributions to size, color, shape and other characteristics of melanocytic naevi in a sample of adolescent twins. Genet. Epidemiol. 16, 40–53 (1999). Zhu, G. et al. A major quantitative-trait locus for mole density is linked to the familial melanoma gene CDKN2A: a maximum-likelihood combined linkage and association analysis in twins and their sibs. Am. J. Hum. Genet. 65, 483–492 (1999). Medland, S.E. et al. Common variants in the trichohyalin gene are associated with straight hair in Europeans. Am. J. Hum. Genet. 85, 750–755 (2009). Teo, Y.Y. et al. A genotype calling algorithm for the Illumina BeadArray platform. Bioinformatics 23, 2741–2746 (2007). Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007). Hayes, B.J., Visscher, P.M. & Goddard, M.E. Increased accuracy of artificial selection by using the realized relationship matrix. Genet. Res. 91, 47–60 (2009). Oliehoek, P.A., Windig, J.J., van Arendonk, J.A. & Bijma, P. Estimating relatedness between individuals in general populations with a focus on their use in conservation programs. Genetics 173, 483–496 (2006). Patterson, H.D. & Thompson, R. Recovery of interblock information when block sizes are unequal. Biometrika 58, 545–554 (1971). Gilmour, A.R., Gogel, B.J., Cullis, B.R. & Thompson, R. ASReml User Guide Release 2.0. (VSN International, Hemel Hempstead, UK, 2006). Wellcome Trust Case Control Consortium et al. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat. Genet. 39, 1329–1337 (2007). Wellcome Trust Case Control Consortium et al. Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls. Nature 464, 713–720 (2010). Vitonis, A.F., Baer, H.J., Hankinson, S.E., Laufer, M.R. & Missmer, S.A. A prospective study of body size during childhood and early adulthood and the incidence of endometriosis. Hum. Reprod. 25, 1325–1334 (2010). Curhan, G.C. & Taylor, E.N. 24-h uric acid excretion and the risk of kidney stones. Kidney Int. 73, 489–496 (2008). Zhao, Z.Z. et al. Genetic variation in tumour necrosis factor and lymphotoxin is not associated with endometriosis in an Australian sample. Hum. Reprod. 22, 2389–2397 (2007). Zhao, Z.Z. et al. Common variation in the fibroblast growth factor receptor 2 gene is not associated with endometriosis risk. Hum. Reprod. 23, 1661–1668 (2008). Mägi, R. & Morris, A.P. GWAMA: software for genome-wide association meta-analysis. BMC Bioinformatics 11, 288 (2010). Purcell, S., Cherny, S.S. & Sham, P.C. Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics 19, 149–150 (2003).

Acknowledgements

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 http://www.wtccc.org.uk. 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. Author information Authors and Affiliations Contributions 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 Ethics declarations Competing interests The authors declare no competing financial interests. Supplementary information Supplementary Text and Figures (download PDF ) Supplemementary Note, Supplementary Tables 1–4 and Supplementary Figures 1–3 (PDF 941 kb) Rights and permissions About this article Cite this article 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). https://doi.org/10.1038/ng.731 Received: Accepted: Published: Issue date: DOI: https://doi.org/10.1038/ng.731 This article is cited by - Whole-exome sequencing reveals candidate high-risk susceptibility genes for endometriosis Human Genomics (2023) - Genetic polymorphisms of Vascular Endothelial Growth Factor (VEGF) associated with endometriosis in Nigerian women Human Genomics (2021) - Integration of genome-wide association study and expression quantitative trait locus mapping for identification of endometriosis-associated genes Scientific Reports (2021) - Molecular signature of eutopic endometrium in endometriosis based on the multi-omics integrative synthesis Journal of Assisted Reproduction and Genetics (2020) - miR-141-3p affects apoptosis and migration of endometrial stromal cells by targeting KLF-12 Pflügers Archiv - European Journal of Physiology (2019)

Text is read by the "Ask this paper" AI Q&A widget below. Extraction quality varies by source — PMC NXML preserves structure cleanly, OA-HTML may include some navigation residue, and OA-PDF can have broken hyphenation. The publisher copy (via DOI) is the canonical version.

My notes (saved in your browser only)

⚙ Ask this paper AI returns verbatim quotes from the full text · source: oa-doi-fallback ⓘ

Answers must be backed by verbatim quotes from this paper's full text. Hallucinated quotes are dropped automatically; if no verbatim passage answers the question, we say so. How this works

Condition tags

mesh:D004715endometriosis

MeSH descriptors

Chromosomes, Human, Pair 15 Endometriosis Genome, Human Genome-Wide Association Study Australia Basic-Leucine Zipper Transcription Factors Basic-Leucine Zipper Transcription Factors Chromosomes, Human, Pair 15 Cohort Studies Endometriosis Female Genetic Loci Genetic Predisposition to Disease Genome, Human Homeobox A10 Proteins Homeodomain Proteins Homeodomain Proteins Humans Odds Ratio Risk Factors

Citation neighborhood

Papers in the corpus that this work cites (lower rings, blue) and that cite this one (upper rings, green). Dot size scales with the paper's in-corpus citation count — bigger dot = more influential within the endo/adeno field. Click a dot to open that paper. [ expand to 2 hops ] — adds papers reached through this work's immediate citers/citees. Heavier; up to 60 extra dots.

References (47)

Cited by (50)

Source provenance

europepmc
last seen: 2026-06-04T01:30:01.192114+00:00
openalex
last seen: 2026-06-04T00:00:01.174412+00:00
pubmed
last seen: 2026-05-13T22:16:54.825375+00:00
License: CC0 · commercial use OK