We conducted a multi-ancestry genome-wide association study of endometriosis and adenomyosis in ∼1.4 million women, including 105,869 cases, aiming to expand endometriosis loci discovery across ancestries, dissect symptom-specific effects, and integrate multi-omic data. We identified 80 genome-wide significant associations, 37 of which are novel, including five loci that are the first ever variants reported for adenomyosis. Fine-mapping and colocalization analyses uncovered causal loci for over 50 endometriosis-related associations. Multi-omics integration revealed that genetic variation influences endometriosis risk through transcriptomic, epigenetic, and proteomic regulation across multiple tissues, converging on pathways involved in immune regulation, tissue remodeling, and cell differentiation. Drug-repurposing analyses highlighted potential therapeutic interventions currently used for breast cancer and preterm birth prevention. Endometriosis polygenic risk interacted with abdominal pain, anxiety, migraine, and nausea. This study advances the understanding of genetic risk factors for endometriosis and provides molecular support for several hypotheses on the disease’s pathogenesis.

R.P. is paid for his editorial work in the journal Complex Psychiatry and received a research grant outside the scope of this study from Alkermes. I.F. is the co-founder and co-owner of Sur180 Therapeutics and the Chief Scientific Officer of Nura Health. The rest of the authors declare no competing interests.

The authors acknowledge support from the National Institutes of Health (RF1 MH132337 to R.P.), the American Foundation for Suicide Prevention (PDF-0-065-23 to J.H.), the MQ Foundation (UFA21\100014 to B.C.M.), Fundacio La Marato de TV3 (202218-31 to B.C.), the Spanish Ministerio de Ciencia, Innovacion y Universidades (projects PID2021-1277760B-I100 and PID2024-158634OB-I00 funded by MICIU/AEI/10.13039/501100011033/ and FEDER-EU to B.C.; PID2022-139740OA-I00 funded by MICIU/AEI/10.13039/501100011033/ and FEDER-EU; RYC2021-033573-I funded by MCIN/AEI/10.13039/501100011033 and by the European Union NextGenerationEU/PRTR to M.M.; RYC2024-050099-I and JDC2024-055161-I funded by MICIU/AEI/10.13039/501100011033 and by FSE+ to D.K. and S.A., respectively; and the Endo-Map project PID2021-12728OB-I00 funded by MICIU/AEI/10.13039/501100011033 and by FEDER-EU to S.A.)), ICREA Academia 2021 (to B.C.), AGAUR (2021SGR-01093 to B.C. and M.M.), and the University of Bergen (International Training Grant to S.L.).We also acknowledge the contribution of the participants and the investigators involved in the UKB, the FinnGen Project, the MVP, the AoU Research Program, the EstBB, BBJ, and all included studies in the International Endogene Consortium GWAS. We would like to thank the research participants and employees of 23andMe, Inc. for making this work possible. The research using UKB resources has been conducted under Application Number 58146. The AoU Research Program is supported by the National Institutes of Health, Office of the Director: Regional Medical Centers: 1 OT2 OD026549; 1 OT2 OD026554; 1 OT2 OD026557; 1 OT2 OD026556; 1 OT2 OD026550; 1 OT2 OD 026552; 1 OT2 OD026553; 1 OT2 OD026548; 1 OT2 OD026551; 1 OT2 OD026555; IAA: AOD 16037; Federally Qualified Health Centers: HHSN 263201600085U; Data and Research Center: 5 U2C OD023196; Biobank: 1 U24 OD023121; The Participant Center: U24 OD023176; Participant Technology Systems Center: 1 U24 OD023163; Communications and Engagement: 3 OT2 OD023205; 3 OT2 OD023206; and Community Partners: 1 OT2 OD025277; 3 OT2 OD025315; 1 OT2 OD025337; 1 OT2 OD025276.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All of Us Research Program provided individual-level data access through the Researcher Workbench (researchallofus.org) and UK Biobank through their Research Analysis Platform (https://www.ukbiobank.ac.uk/use-our-data/research-analysis-platform/). The other cohorts investigated were analyzed using publicly available genome-wide association statistics.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

The genome-wide association statistics generated by the current study will be made available in Zenodo at the time of publication.