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In this genetic study (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009544,513), we expand the number of genetic loci from 16 to 29, and additionally identify 31 associated plasma proteins. Many risk-increasing loci were associated with later age at menopause, underscoring the reproductive longevity related to an increased oocyte number and\/or availability across the lifespan. Hormonal regulation in the etiology of this condition, through metabolic and reproductive features, was emphasized. The proteomic analysis highlighted metabolic biology known to be related to PCOS. A polygenic risk score (PRS) was associated with adverse cardiometabolic outcomes, with differing relevance of testosterone and body mass index in women and men. Finally, while oligo-anovulation and anovulatory infertility are features of PCOS, we observed no impact of PCOS susceptibility on childlessness. We suggest that PCOS susceptibility confers balanced pleiotropic influences on fertility in women, and life-long adverse metabolic consequences in both sexes.\n                  <\/jats:p>","DOI":"10.1038\/s41588-026-02543-9","type":"journal-article","created":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T09:02:04Z","timestamp":1776934924000},"page":"1040-1050","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Genomic analyses implicate hormonal and metabolic dysregulation in polycystic ovary syndrome"],"prefix":"10.1038","volume":"58","author":[{"given":"Loes M. 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S.B. reports ownerships in Intomics A\/S, Hoba Therapeutics Aps, Novo Nordisk A\/S, Lundbeck A\/S and ALK abello A\/S. G.T., U.T., K.S. and U.S. are employees of deCODE genetics\/Amgen. M.I.M. serves on advisory panels for Pfizer and Novo Nordisk; has received honoraria from Pfizer, Novo Nordisk and Eli Lilly; has received research funding from Pfizer, Novo Nordisk, Eli Lilly, AstraZeneca, Sanofi Aventis, Boehringer Ingelheim, Merck, Roche, Janssen, Takeda and Servier; and is now an employee of Genentech and a holder of Roche stock. J.L. has received consultancy fees from Danone, Metagenics, Titus Healthcare, Roche and Euroscreen. R.A. has received consultancy fees from Spruce Biosciences, Fortress Biotech, Rani Therapeutics, Core Access Surgical Technologies, Proera and May Health, and has equity in Arora Forge Advisors and Martin Imaging. M.O.G. has served on an advisory board for Nestle Health Science. B.C.F. has received fees and\/or grant support during the last 4 years from the following organizations: Bain Capital, Controversies in Obstetrics & Gynecology & Infertility, Dutch Heart Foundation (Nederlandse Hartstichting), Elsevier, European Society of Human Reproduction and Embryology, Ferring, International Federation of Fertility Societies, London Women\u2019s Clinic, Myovant, the Netherlands Organisation for Health Research and Development (ZonMW), Pantharei Bioscience, Partners Group, PregLem\/Gideon Richter, Reproductive Biomedicine Online, Shieldler and UpToDate. T.D.S. is a cofounder and shareholder of Zoe. J.N.H. has equity in Camp4 Therapeutics. K.A.K. and J.R.B.P. are employees and shareholders of Insmed. J.R.B.P. receives research funding from GSK. Y.Z. was a UK University worker at GSK. J.A.V. has received royalties from AMH assays, paid to the institute\/laboratory, with no personal financial gain. 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