TY - JOUR
T1 - Genomic analyses implicate hormonal and metabolic dysregulation in polycystic ovary syndrome
AU - Genes and Health Research Team
AU - DBDS Genomic Consortium
AU - 23andMe Research Team
AU - Moolhuijsen, Loes M.E.
AU - Zhu, Jia
AU - Mullin, Benjamin H.
AU - Pujol-Gualdo, Natàlia
AU - Actkins, Ky’Era V.
AU - Mack, Jasmine A.
AU - Rao, Hridya
AU - Trivedi, Bhavi
AU - Kentistou, Katherine A.
AU - Zhao, Yajie
AU - Westergaard, David
AU - Tyrmi, Jaakko S.
AU - Thorleifsson, Gudmar
AU - Zhang, Yanfei
AU - Wittemans, Laura
AU - DeVries, Amber
AU - Brewer, Kelly
AU - Sisk, Ryan
AU - Danning, Rebecca
AU - Preuss, Michael H.
AU - Jones, Michelle R.
AU - Ruth, Katherine S.
AU - Andersen, Marianne
AU - Azziz, Ricardo
AU - Banasik, Karina
AU - Boehnke, Michael
AU - Broer, Linda
AU - Brunak, Søren
AU - Chan, Yee Ming
AU - Chasman, Daniel I.
AU - Daly, Mark
AU - Ehrmann, David A.
AU - Fauser, Bart C.
AU - Fritsche, Lars G.
AU - Hayes, M. Geoffrey
AU - He, Chunyan
AU - Huang, Hongyan
AU - Kowalska, Irina
AU - Kraft, Peter
AU - Legro, Richard S.
AU - Lin, Nan
AU - Loos, Ruth J.
AU - Louwers, Yvonne V.
AU - Magi, Reedik
AU - McCarthy, Mark I.
AU - Morin-Papunen, Laure
AU - Morrison, Jean V.
AU - Nadkarni, Girish N.
AU - Abul-Husn, Noura S.
AU - Dunaif, Andrea
N1 - Publisher Copyright:
© The Author(s) 2026.
PY - 2026/5
Y1 - 2026/5
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/105036692907
U2 - 10.1038/s41588-026-02543-9
DO - 10.1038/s41588-026-02543-9
M3 - Article
AN - SCOPUS:105036692907
SN - 1061-4036
VL - 58
SP - 1040
EP - 1050
JO - Nature Genetics
JF - Nature Genetics
IS - 5
ER -