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

By Rahmioglu Nilufer, Banasik Karina, Christofidou Paraskevi, Danning Rebecca, Galarneau Genevieve, Giri Ayush, MacGregor Stuart, Mortlock Sally, Sapkota Yadav, Schork J Andrew, Sobalska-Kwapis Marta, Stefansdottir Lilja, Turman Constance, Uimari Outi, Adachi Sosuke, Andrews Shan, Arnadottir Ragnheidur, Burgdorf S Kristoffer, Campbell Archie, Cheuk SK Cecilia, Clementi Caterina, Cook James, De Vivo Immaculata, DiVasta Amy, O Dorien, Edwards Todd, Fontanillas Pierre, Fung N Jenny, Geirsson T Reynir, Girling Jane, Harris R Holly, Holdsworth-Carson Sarah, Houshdaran Sahar, Hu-Seliger Tina, Jaqrvelin Marjo-Riitta, Kepka Ewa, Kulig Bartosz, Laufer R Marc, Law Matthew, Low Siew-Kee, Mangino Massimo, Marciniak Blazej, Matalliotaki Charoula, Matalliotakis Michail, Murray D Alison, Nezhat Camran, Nõukas Margit, Olsen Catherine, Padmanabhan Sandosh, Paranjpe Manish, Parfitt David-Emlyn, Peters Maire, Polak Grzegorz, Porteous J David, Romanowicz Hanna, Saare Merli, Shafrir Amy, Siewierska-Górska Anna, Skarp Sini, Slomka Marcin, Smith H Blair, Smolarz Beata, Szaflik Tomasz, Szyllo Krzysztof, Terry Kathyrn, Thorleifsson Gudmar, Tomassetti Carla, Vanhie Arne, Vincent Katy, Vitonis Allison, Werge Thomas, DBDS Genetic Consortium, S Andersen, K Banasik, S Brunak, KS Burgdorf, C Erikstrup, TF Hansen, H Hjalgrim, G Jemec, P Jennum, KR Nielsen, M Nyegaard, HM Paarup, OB Pedersen, M Petersen, E Sorensen, H Ullum, T Werge, D Gudbjartsson, Kári Stefánsson, H. Stefansson, U Þorsteinsdottir, iPSYCH-Broad Consortium, PB Mortensen, DM Hougaard, AD Borglum, the Celmatix Research Team, the 23andMe Research Team, Chasman I Daniel, D’Hooghe Thomas, Giudice C Linda, Goulielmos N George, Hapangama K Dharani, Hayward Caroline, Horne W Andrew, Kamatani Yoichiro, Kubo Michiaki, Martikainen Hannu, Rogers AW Peter, Saunders T Philippa, Sirota Marina, Spector Tim, Strapagiel Dominik, Tung Y Joyce, Whiteman David, Becker M Christian, Salumets Andres, Magi Reedik, Kraft Peter, Nyegaard Mette, Nyholt R Dale, Steinthorsdottir Valgerdur, Stefansson Kari, Velez-Edwards R Digna, Yurttas Beim Piraye, Missmer A Stacey, Montgomery W Grant, Morris P Andrew, Zondervan T Krina

Posted 07 Sep 2018
bioRxiv DOI: 10.1101/406967

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<5x10-8), 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<1.28x10-3) 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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