Large-scale genome-wide association meta-analysis of endometriosis reveals 13 novel loci and genetically-associated comorbidity with other pain conditions

Rahmioglu Nilufer, Banasik Karina, Christofidou Paraskevi, D. Larson Rebecca, Galarneau Genevieve, Ayush Giri, Giri Ayush, Stuart MacGregor, Mortlock Sally, Sally Mortlock, S. P. S. Yadav, Sapkota Yadav, Schork J Andrew, Sobalska-Kwapis Marta, Stefansdottir Lilja, T. J. Constance, Uimari Outi, Sosuke Adachi, Andrews Shan, Arnadottir Ragnheidur, Kristoffer Sølvsten Burgdorf, Campbell Archie, Cheuk SK Cecilia, Clementi Caterina, Cook James, De Vivo Immaculata, D. Amy, O Dorien, Edwards Todd, Fontanillas Pierre, Fung N Jenny, Geirsson T Reynir, Jane E. Girling, Harris R Holly, Holdsworth-Carson Sarah, Houshdaran Sahar, Hu-Seliger Tina, Jaqrvelin Marjo-Riitta, Kepka Ewa, Kulig Bartosz, Laufer R Marc, Matthew Law, Law Matthew, Low Siew-Kee, Mangino Massimo, Marciniak Blazej, Charoula Matalliotaki, Michail Matalliotakis, Murray D Alison, Nezhat Camran, Nõukas Margit, O Sainte Catherine, Padmanabhan Sandosh, Paranjpe Manish, Parfitt David-Emlyn, Peters Maire, Polak Grzegorz, Porteous David, Hanna Romanowicz, Saare Merli, Shafrir Amy, Siewierska-Górska Anna, Sini Skarp, Slomka Marcin, Smith Blair, Beata Smolarz, Szaflik Tomasz, Tomasz Składzień, S. Krzysztof, Terry Kathyrn, Guðmar Þorleifsson, Carla Tomassetti, Vanhie Arne, Katy Vincent, Vincent Katy, Vitonis Allison, Werge Thomas, S Andersen, Karina Banasik, Søren Brunak, KS Burgdorf, Christian Erikstrup, TF Hansen, Helle Hjalgrim, Gregor B. E. Jemec, Poul Jennum, KR Nielsen, Mette Nyegaard, HM Paarup, Ole Birger Pedersen, Maria Skaalum Petersen, Erik Sørensen, Henrik Ullum, Thomas Werge, Daníel F. Guðbjartsson, Kāri Stefánsson, Hreinn Stefánsson, Unnur Þorsteinsdóttir, PB Mortensen, DM Hougaard, AD Borglum, Chasman Daniel, D. Thomas, Giudice C Linda, Goulielmos N George, Hapangama K Dharani, Hayward Caroline, Horne W Andrew, Yoichiro Kamatani, Michiaki Kubo, Martikainen Hannu, Rogers AW Peter, Saunders T Philippa, Sirota Marina, Spector Tim, Dominik Strapagiel, Tung Y Joyce, W. G. Stanton David, Becker M Christian, Salumets Andres, Mägi Reedik, K Peter, Nyholt R Dale, Steinthorsdottir Valgerdur, Velez-Edwards R Digna, Yurttas Beim Piraye, Missmer A Stacey, Montgomery W Grant, Morris P Andrew, Krina T. Zondervan
In: bioRxiv · 2018 · doi:10.1101/406967 · W2891063725
preprint OA: green CC0 ⤵ 29 in-corpus citations
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This genome-wide association meta-analysis identified 27 genetic loci for endometriosis, including 13 novel ones, and found genetic correlations with other pain conditions, osteoarthritis, diabetes, and menstrual traits.

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Abstract

Abstract Endometriosis is a common complex inflammatory condition characterised by the presence of endometrium-like tissue outside the uterus, mainly in the pelvic area. It is associated with chronic pelvic pain and infertility, and its pathogenesis remains poorly understood. The disease is typically classified according to the revised American Fertility Society (rAFS) 4-stage surgical assessment system, although stage does not correlate well with symptomatology or prognosis. Previously identified genetic variants mainly are associated with stage III/IV disease, highlighting the need for further phenotype-stratified analysis that requires larger datasets. We conducted a meta-analysis of 15 genome-wide association studies (GWAS) and a replication analysis, including 58,115 cases and 733,480 controls in total, and sub-phenotype analyses of stage I/II, stage III/IV and infertility-associated endometriosis cases. This revealed 27 genetic loci associated with endometriosis at the genome-wide p-value threshold (P<5×10 −8 ), 13 of which are novel and an additional 8 novel genes identified from gene-based association analyses. Of the 27 loci, 21 (78%) had greater effect sizes in stage III/IV disease compared to stage I/II, 1 (4%) had greater effect size in stage I/II compared to stage III/IV and 17 (63%) had greater effect sizes when restricted to infertility-associated endometriosis cases compared to overall endometriosis. These results suggest that specific variants may confer risk for different sub-types of endometriosis through distinct pathways. Analyses of genetic variants underlying different pain symptoms reported in the UK Biobank showed that 7/9 had positive significant (p<1.28×10 3 ) positive genetic correlations with endometriosis, suggesting a genetic basis for sensitivity to pain in general. Additional conditions with significant positive genetic correlations with endometriosis included uterine fibroids, excessive and irregular menstrual bleeding, osteoarthritis, diabetes as well as menstrual cycle length and age at menarche. These results provide a basis for fine-mapping of the causal variants at these 27 loci, and for functional follow-up to understand their contribution to endometriosis and its potential subtypes.

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endometriosischronic_pelvic_paininfertility

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