Genomic analyses implicate hormonal and metabolic dysregulation in polycystic ovary syndrome

Moolhuijsen, Loes M.E.; Zhu, Jia; Mullin, Benjamin H.; Pujol-Gualdo, Natàlia; Actkins, Ky’Era V.; Mack, Jasmine A.; Rao, Hridya; Trivedi, Bhavi; Kentistou, Katherine A.; Zhao, Yajie; Westergaard, David; Tyrmi, Jaakko S.; Thorleifsson, Gudmar; Zhang, Yanfei; Wittemans, Laura; DeVries, Amber; Brewer, Kelly; Sisk, Ryan; Danning, Rebecca; Preuss, Michael H.; Jones, Michelle R.; Ruth, Katherine S.; Andersen, Marianne; Azziz, Ricardo; Banasik, Karina; Boehnke, Michael; Broer, Linda; Brunak, Søren; Chan, Yee Ming; Chasman, Daniel I.; Daly, Mark; Ehrmann, David A.; Fauser, Bart C.; Fritsche, Lars G.; Hayes, M. Geoffrey; He, Chunyan; Huang, Hongyan; Kowalska, Irina; Kraft, Peter; Legro, Richard S.; Lin, Nan; Loos, Ruth J.; Louwers, Yvonne V.; Magi, Reedik; McCarthy, Mark I.; Morin-Papunen, Laure; Morrison, Jean V.; Morton, Cynthia; Nadkarni, Girish N.; Laivuori, Hannele (2026)
 
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Moolhuijsen, Loes M.E.
Zhu, Jia
Mullin, Benjamin H.
Pujol-Gualdo, Natàlia
Actkins, Ky’Era V.
Mack, Jasmine A.
Rao, Hridya
Trivedi, Bhavi
Kentistou, Katherine A.
Zhao, Yajie
Westergaard, David
Tyrmi, Jaakko S.
Thorleifsson, Gudmar
Zhang, Yanfei
Wittemans, Laura
DeVries, Amber
Brewer, Kelly
Sisk, Ryan
Danning, Rebecca
Preuss, Michael H.
Jones, Michelle R.
Ruth, Katherine S.
Andersen, Marianne
Azziz, Ricardo
Banasik, Karina
Boehnke, Michael
Broer, Linda
Brunak, Søren
Chan, Yee Ming
Chasman, Daniel I.
Daly, Mark
Ehrmann, David A.
Fauser, Bart C.
Fritsche, Lars G.
Hayes, M. Geoffrey
He, Chunyan
Huang, Hongyan
Kowalska, Irina
Kraft, Peter
Legro, Richard S.
Lin, Nan
Loos, Ruth J.
Louwers, Yvonne V.
Magi, Reedik
McCarthy, Mark I.
Morin-Papunen, Laure
Morrison, Jean V.
Morton, Cynthia
Nadkarni, Girish N.
Laivuori, Hannele
2026

Nature Genetics
doi:10.1038/s41588-026-02543-9
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https://urn.fi/URN:NBN:fi:tuni-202607088235

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Peer reviewed
Tiivistelmä
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.
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