Multi-ancestry genome-wide association and integrated multi-omics analyses of endometriosis and its clinical manifestations

Endometriosis is a chronic systemic disease affecting ~10% of women, yet its genetic basis and molecular mechanisms remain poorly understood. Hence, here we conducted a genome-wide association study of endometriosis and adenomyosis in ~1.4 million women, including 105,869 cases, aiming to expand loci discovery across ancestries, dissect symptom-specific effects and integrate multi-omic data. We identified 80 genomic regions associated with endometriosis risk, including 37 new loci, of which 5 are also associated with adenomyosis. We identified putative causal variants underlying over 50 of these associations. Transcriptomic, epigenetic and proteomic analyses across tissues linked endometriosis risk to pathways involved in cell differentiation, immune and hormonal regulation, tissue remodeling and inflammation. Drug-repurposing analyses highlighted potential treatments currently used for breast cancer, contraception and preterm birth prevention. Endometriosis polygenic risk interacted with abdominal pain, anxiety, migraine and nausea. This study advances understanding of genetic risk factors for endometriosis and provides molecular support for several hypotheses on its pathogenesis. This is a preview of subscription content, access via your institution Access options Access Nature and 54 other Nature Portfolio journals Get Nature+, our best-value online-access subscription 27,99 € / 30 days cancel any time 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 Data availability The genome-wide association statistics generated by the current study and the endometriosis polygenic score variants and weights are available on Zenodo (https://doi.org/10.5281/zenodo.18983492)104. GWAS-data-related cohorts included in this study were derived from the following sources: AoU, https://workbench.researchallofus.org/; FinnGen, https://www.finngen.fi/en/access_results; MVP, https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs001672.v12.p1; UKB, https://www.ukbiobank.ac.uk/; BBJ, https://pheweb.jp/downloads; EstBB, https://www.ebi.ac.uk/gwas/; IEGC, https://www.ebi.ac.uk/gwas/; and 23andMe—full GWAS summary statistics for the 23andMe dataset will be made available through 23andMe to qualified researchers under an agreement with 23andMe that protects the privacy of the 23andMe participants, https://www.biorxiv.org/content/10.1101/401448v1.full. Code availability The study used the following computational packages: METAL (v3), https://github.com/statgen/METAL; GCTA-COJO (v1.94.1), https://yanglab.westlake.edu.cn/software/gcta/#COJO; PAINTOR (v3), https://github.com/gkichaev/PAINTOR_V3.0; LDSC (v1), https://github.com/bulik/ldsc; PRS-CS (v1.1.0), https://github.com/getian107/PRScs; PLINK2 (v2.0), https://www.cog-genomics.org/plink/2.0/; MetaXcan (v0.8.0), https://github.com/hakyimlab/MetaXcan; FUSION (v1), https://github.com/gusevlab/fusion_twas; HyPrColoc (v0.0.2), https://github.com/cnfoley/hyprcoloc; MixeR (v1), https://github.com/precimed/mixer; LCV (v1), https://github.com/lukejoconnor/LCV; TwoSampleMR (v0.7.0), https://mrcieu.github.io/TwoSampleMR/; HyPrColoc (v0.0.2), https://github.com/jrs95/hyprcoloc; MetaXcan (v0.8.1), https://github.com/hakyimlab/MetaXcan; SMR (v1.4.0), https://yanglab.westlake.edu.cn/software/smr/#Overview; GSA-MiXeR (v2.2.1), https://github.com/precimed/gsa-mixer; DRUGSETS (v1), https://github.com/nybell/drugsets; and Gene2drug (v1), https://gene2drug.tigem.it/about.php.

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We would 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.), ‘Fundació La Marató de TV3’ (202218-31 to B.C.), the Spanish ‘Ministerio de Ciencia, Innovación 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. Aranda, respectively; and the Endo-Map project PID2021-12728OB-I00 funded by MICIU/AEI/10.13039/501100011033 and by FEDER-EU to S. Altmäe). The authors also acknowledge support from the Research Council of Norway through its Centers of Excellence funding scheme (project 262700), and cofunded by the European Union (ERC, BIOSFER, project 101071773 to S.L.), 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 IEGC GWAS. The authors thank the research participants and employees of 23andMe for making this work possible. The research using UKB resources has been conducted under application 58146 (PI to R.P.). 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 and 3 OT2 OD023206) and Community Partners (1 OT2 OD025277, 3 OT2 OD025315, 1 OT2 OD025337 and 1 OT2 OD025276). Author information Authors and Affiliations Contributions D.K. and R.P. designed the study, supervised the analyses and wrote the initial draft of the manuscript. D.K., J.H., S.L., S. Aranda, D.Q., D.D., Q.C., Z.X., Z.M., E.F., S.K., B.C.-M. and R.P. conducted computational and statistical analyses. D.K., J.H., S.L., S. Aranda, D.Q., D.D., Q.C., Z.X., Z.M., E.F., S.K., B.C., I.F., S. Altmäe, M.M., B.C.-M. and R.P. interpreted the results, provided comments and revised the manuscript. R.P. obtained the primary funding for the study. Corresponding authors Ethics declarations Competing interests 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 cofounder and co-owner of Sur180 Therapeutics, which is developing a new treatment for endometriosis, and the Chief Scientific Officer of Nura Health, which is developing a noninvasive diagnostic solution for the disease. The other authors declare no competing interests. Peer review Peer review information Nature Genetics thanks Sally Mortlock and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available. Additional information Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Extended data Extended Data Fig. 1 Ancestry-specific GWAS of endometriosis combined definition (cases identified through self-reported information and electronic health records). a–d, Manhattan plots are shown for African (AFR, a; ncases = 2,481 and ncontrols = 54,671), Admixed American (AMR, b; ncases = 1,752 and ncontrols = 37,871), East Asian (EAS, c; ncases = 2,044 and ncontrols = 87,823), and European (EUR, d; ncases = 99,407 and ncontrols = 1,093,534) populations. Each point represents the P-value from a fixed-effects meta-analysis (weighted by sample size and P-value using METAL) of two-sided logistic regression tests of association between individual genetic variants and the phenotype across contributing cohorts, ordered by genomic position on the x axis and shown as −log10(P-value) on the y axis. The dashed line represents the genome-wide significance threshold (P < 5 × 10−8), based on Bonferroni multiple testing correction. Extended Data Fig. 2 European (EUR) ancestry GWAS of endometriosis subtypes based on electronic health records and self-reported data. a–c, Manhattan plots are shown for clinically diagnosed endometriosis (a; ncases = 36,695 and ncontrols = 567,775), self-reported endometriosis (b; ncases = 50,867 and ncontrols = 528,391), and endometriosis excluding adenomyosis (c; ncases = 6,627 and ncontrols = 283,316). Each point represents the P-value from a fixed-effects meta-analysis (weighted by sample size and P-value using METAL) of two-sided logistic regression tests of association between individual genetic variants and the phenotype across contributing cohorts, ordered by genomic position on the x axis and shown as −log10(P-value) on the y axis. The dashed line represents the genome-wide significance threshold (P < 5 × 10−8), based on Bonferroni multiple testing correction. Supplementary information Supplementary Information (download PDF ) Supplementary Note and Figs. 1–3. Supplementary Tables (download XLSX ) Supplementary Tables 1–34. Rights and permissions Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. About this article Cite this article Koller, D., He, J., Løkhammer, S. et al. Multi-ancestry genome-wide association and integrated multi-omics analyses of endometriosis and its clinical manifestations. Nat Genet 58, 1051–1061 (2026). https://doi.org/10.1038/s41588-026-02582-2 Received: Accepted: Published: Version of record: Issue date: DOI: https://doi.org/10.1038/s41588-026-02582-2