Large-scale genome-wide association meta-analysis of endometriosis reveals 13 novel loci and genetically-associated comorbidity with other pain conditions
Authors: Nilufer Rahmioglu , Karina Banasik , Paraskevi Christofidou , Rebecca Danning , Genevieve Galarneau , Ayush Giri , Stuart MacGregor , Sally Mortlock , Yadav Sapkota , Andrew Schork J , Marta Sobalska-Kwapis , Lilja Stefansdottir , Constance Turman , Outi Uimari , Sosuke Adachi , Shan Andrews , Ragnheidur Arnadottir , Kristoffer Burgdorf S , Archie Campbell , Cecilia Cheuk SK , Caterina Clementi , James Cook , Immaculata De Vivo , Amy DiVasta , Dorien O , Todd Edwards , Pierre Fontanillas , Jenny Fung N , Reynir Geirsson T , Jane Girling , Holly Harris R , Sarah Holdsworth-Carson , Sahar Houshdaran , Tina Hu-Seliger , Marjo-Riitta Jaqrvelin , Ewa Kepka , Bartosz Kulig , Marc Laufer R , Matthew Law , Siew-Kee Low , Massimo Mangino , Blazej Marciniak , Charoula Matalliotaki , Michail Matalliotakis , Alison Murray D , Camran Nezhat , Margit Nõukas , Catherine Olsen , Sandosh Padmanabhan , Manish Paranjpe , David-Emlyn Parfitt , Maire Peters , Grzegorz Polak , David Porteous J , Hanna Romanowicz , Merli Saare , Amy Shafrir , Anna Siewierska-Górska , Sini Skarp , Marcin Slomka , Blair Smith H , Beata Smolarz , Tomasz Szaflik , Krzysztof Szyllo , Kathyrn Terry , Gudmar Thorleifsson , Carla Tomassetti , Arne Vanhie , Katy Vincent , Allison Vitonis , Thomas Werge ,   DBDS Genetic Consortium, Andersen S , Banasik K , Brunak S , Burgdorf KS , Erikstrup C , Hansen TF , Hjalgrim H , Jemec G , Jennum P , Nielsen KR , Nyegaard M , Paarup HM , Pedersen OB , Petersen M , Sorensen E , Ullum H , Werge T , Gudbjartsson D , Stefansson K , Stefansson H , Þorsteinsdottir U ,   iPSYCH-Broad Consortium, Mortensen PB , Hougaard DM , Borglum AD ,   the Celmatix Research Team,   the 23andMe Research Team, Daniel Chasman I , Thomas D’Hooghe , Linda Giudice C , George Goulielmos N , Dharani Hapangama K , Caroline Hayward , Andrew Horne W , Yoichiro Kamatani , Michiaki Kubo , Hannu Martikainen , Peter Rogers AW , Philippa Saunders T , Marina Sirota , Tim Spector , Dominik Strapagiel , Joyce Tung Y , David Whiteman , Christian Becker M , Andres Salumets , Reedik Magi , Peter Kraft , Mette Nyegaard , Dale Nyholt R , Valgerdur Steinthorsdottir , Kari Stefansson , Digna Velez-Edwards R , Piraye Yurttas Beim , Stacey Missmer A , Grant Montgomery W , Andrew Morris P , Krina Zondervan T 
Published: September 2018

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<1.28×103) 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.