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<p>Polycystic ovary syndrome (PCOS) and its underlying features remain poorly understood. In this genetic study (<i>n</i> = 544,513), 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.</p>

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Genomic analyses implicate hormonal and metabolic dysregulation in polycystic ovary syndrome

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月23日

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  • Loes M. E. Moolhuijsen,
  • Jia Zhu,
  • Benjamin H. Mullin,
  • Natàlia Pujol-Gualdo,
  • Ky’Era V. Actkins,
  • Jasmine A. Mack,
  • Hridya Rao,
  • Bhavi Trivedi,
  • Katherine A. Kentistou,
  • Yajie Zhao,
  • David Westergaard,
  • Jaakko S. Tyrmi,
  • Gudmar Thorleifsson,
  • Yanfei Zhang,
  • Laura Wittemans,
  • Amber DeVries,
  • Kelly Brewer,
  • Ryan Sisk,
  • Rebecca Danning,
  • Michael H. Preuss,
  • Michelle R. Jones,
  • Katherine S. Ruth,
  • Marianne Andersen,
  • Ricardo Azziz,
  • Karina Banasik,
  • Michael Boehnke,
  • Linda Broer,
  • Søren Brunak,
  • Yee-Ming Chan,
  • Daniel I. Chasman,
  • Mark Daly,
  • David A. Ehrmann,
  • Bart C. Fauser,
  • Lars G. Fritsche,
  • M. Geoffrey Hayes,
  • Chunyan He,
  • Hongyan Huang,
  • Irina Kowalska,
  • Peter Kraft,
  • Richard S. Legro,
  • Nan Lin,
  • Ruth J. Loos,
  • Yvonne V. Louwers,
  • Reedik Magi,
  • Mark I. McCarthy,
  • Laure Morin-Papunen,
  • Jean V. Morrison,
  • Cynthia Morton,
  • Girish N. Nadkarni,
  • Benjamin M. Neale,
  • Henriette Svarre Nielsen,
  • Mette Nyegaard,
  • Sisse R. Ostrowski,
  • Ole B. V. Pedersen,
  • Erik Sørensen,
  • Christina Mikkelsen,
  • Christian Erikstrup,
  • Kathrine A. Kaspersen,
  • Mie T. Bruun,
  • Bitten Aagaard,
  • Henrik Ullum,
  • Barbara Obermayer-Pietsch,
  • Aarno Palotie,
  • Mary P. Reeve,
  • Andres Salumets,
  • Richa Saxena,
  • Timothy D. Spector,
  • Bronwyn G. A. Stuckey,
  • Unnur Thorsteinsdottir,
  • André G. Uitterlinden,
  • Margrit Urbanek,
  • Sebastian Zöllner,
  • David A. van Heel,
  • Henrik Ullum,
  • Adam Auton,
  • Alan Kwong,
  • Anjali J. Shastri,
  • Barry Hicks,
  • Catherine H. Weldon,
  • David A. Hinds,
  • Emily DelloRusso,
  • Emily M. Rios,
  • Joyce Y. Tung,
  • Kahsaia de Brito,
  • Katelyn Kukar Bond,
  • Keng-Han Lin,
  • Matthew H. McIntyre,
  • Matthew J. Kmiecik,
  • Qiaojuan Jane Su,
  • Robert K. Bell,
  • Sayantan Das,
  • Shubham Saini,
  • Stella Aslibekyan,
  • Vinh Tran,
  • Wanwan Xu,
  • Alisa P. Lehman,
  • Noura S. Abul-Husn,
  • R. Ryanne Wu,
  • Rebecca M. K. Berns,
  • Ruth I. Tennen,
  • Stacey B. Detweiler,
  • Aditya Ambati,
  • Anna Guan,
  • Bertram L. Koelsch,
  • Chris German,
  • Éadaoin Harney,
  • Ethan M. Jewett,
  • G. David Poznik,
  • James R. Ashenhurst,
  • Jingran Wen,
  • Peter R. Wilton,
  • Steven J. Micheletti,
  • William A. Freyman,
  • David A. van Heel,
  • Joel N. Hirschhorn,
  • Kari Stefansson,
  • John R. B. Perry,
  • Unnur Styrkarsdottir,
  • Scott G. Wilson,
  • Terhi Piltonen,
  • Triin Laisk,
  • Marjo-Riitta Jarvelin,
  • Kharis Burns,
  • Anne E. Justice,
  • Hannele Laivuori,
  • Ken K. Ong,
  • Mark O. Goodarzi,
  • Lea K. Davis,
  • Andrea Dunaif,
  • Cecilia M. Lindgren,
  • Joop S. E. Laven,
  • Stephen Franks,
  • Jenny A. Visser,
  • Corrine K. Welt,
  • Tugce Karaderi,
  • Felix R. Day

摘要

Polycystic ovary syndrome (PCOS) and its underlying features remain poorly understood. In this genetic study (n = 544,513), 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.