Genomic analyses implicate hormonal and metabolic dysregulation in polycystic ovary syndrome

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; Sayantan Das; Robert K. Bell; Joyce Y. Tung; Catherine H. Weldon; 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; Genes and Health Research Team; DBDS Genomic Consortium; 23andMe Research Team; Felix R. Day

doi:10.1038/s41588-026-02543-9

Genomic analyses implicate hormonal and metabolic dysregulation in polycystic ovary syndrome

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. PreussMichelle 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, Sayantan Das, Robert K. Bell, Joyce Y. Tung, Catherine H. Weldon, 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^*, Genes and Health Research Team, DBDS Genomic Consortium, 23andMe Research Team, Felix R. Day^*

^*Corresponding author af dette arbejde

Abstract

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.

Originalsprog	Engelsk
Tidsskrift	Nature Genetics
ISSN	1061-4036
DOI	https://doi.org/10.1038/s41588-026-02543-9
Status	E-pub ahead of print - 2026

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10.1038/s41588-026-02543-9Licens: CC BY

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Moolhuijsen, L. M. E., Zhu, J., Mullin, B. H., Pujol-Gualdo, N., Actkins, KE. V., Mack, J. A., Rao, H., Trivedi, B., Kentistou, K. A., Zhao, Y., Westergaard, D., Tyrmi, J. S., Thorleifsson, G., Zhang, Y., Wittemans, L., DeVries, A., Brewer, K., Sisk, R., Danning, R., ... Day, F. R. (2026). Genomic analyses implicate hormonal and metabolic dysregulation in polycystic ovary syndrome. Nature Genetics. Advance online publication. https://doi.org/10.1038/s41588-026-02543-9

Moolhuijsen, LME, Zhu, J, Mullin, BH, Pujol-Gualdo, N, Actkins, KEV, Mack, JA, Rao, H, Trivedi, B, Kentistou, KA, Zhao, Y, Westergaard, D, Tyrmi, JS, Thorleifsson, G, Zhang, Y, Wittemans, L, DeVries, A, Brewer, K, Sisk, R, Danning, R, Preuss, MH, Jones, MR, Ruth, KS, Andersen, M, Azziz, R, Banasik, K, Boehnke, M, Broer, L, Brunak, S, Chan, YM, Chasman, DI, Daly, M, Ehrmann, DA, Fauser, BC, Fritsche, LG, Hayes, MG, He, C, Huang, H, Kowalska, I, Kraft, P, Legro, RS, Lin, N, Loos, RJ, Louwers, YV, Magi, R, McCarthy, MI, Morin-Papunen, L, Morrison, JV, Morton, C, Nadkarni, GN, Neale, BM, Nielsen, HS, Nyegaard, M, Ostrowski, SR, Pedersen, OBV, Sørensen, E , Mikkelsen, C, Erikstrup, C, Kaspersen, KA, Bruun, MT, Aagaard, B, Ullum, H, Obermayer-Pietsch, B, Palotie, A, Reeve, MP, Salumets, A, Saxena, R, Spector, TD, Stuckey, BGA, Thorsteinsdottir, U, Uitterlinden, AG, Urbanek, M, Zöllner, S, van Heel, DA, Das, S, Bell, RK, Tung, JY, Weldon, CH, van Heel, DA, Hirschhorn, JN, Stefansson, K, Perry, JRB, Styrkarsdottir, U, Wilson, SG, Piltonen, T, Laisk, T, Jarvelin, MR, Burns, K, Justice, AE, Laivuori, H, Ong, KK, Goodarzi, MO, Davis, LK, Dunaif, A, Lindgren, CM, Laven, JSE, Franks, S, Visser, JA, Welt, CK, Karaderi, T, Genes and Health Research Team, DBDS Genomic Consortium, 23andMe Research Team & Day, FR 2026, 'Genomic analyses implicate hormonal and metabolic dysregulation in polycystic ovary syndrome', Nature Genetics. https://doi.org/10.1038/s41588-026-02543-9

@article{12e9b7d85340420dae2e5d8cc093f026,

title = "Genomic analyses implicate hormonal and metabolic dysregulation in polycystic ovary syndrome",

abstract = "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.",

author = "Moolhuijsen, \{Loes M.E.\} and Jia Zhu and Mullin, \{Benjamin H.\} and Nat{\`a}lia Pujol-Gualdo and Actkins, \{Ky{\textquoteright}Era V.\} and Mack, \{Jasmine A.\} and Hridya Rao and Bhavi Trivedi and Kentistou, \{Katherine A.\} and Yajie Zhao and David Westergaard and Tyrmi, \{Jaakko S.\} and Gudmar Thorleifsson and Yanfei Zhang and Laura Wittemans and Amber DeVries and Kelly Brewer and Ryan Sisk and Rebecca Danning and Preuss, \{Michael H.\} and Jones, \{Michelle R.\} and Ruth, \{Katherine S.\} and Marianne Andersen and Ricardo Azziz and Karina Banasik and Michael Boehnke and Linda Broer and S{\o}ren Brunak and Chan, \{Yee Ming\} and Chasman, \{Daniel I.\} and Mark Daly and Ehrmann, \{David A.\} and Fauser, \{Bart C.\} and Fritsche, \{Lars G.\} and Hayes, \{M. Geoffrey\} and Chunyan He and Hongyan Huang and Irina Kowalska and Peter Kraft and Legro, \{Richard S.\} and Nan Lin and Loos, \{Ruth J.\} and Louwers, \{Yvonne V.\} and Reedik Magi and McCarthy, \{Mark I.\} and Laure Morin-Papunen and Morrison, \{Jean V.\} and Cynthia Morton and Nadkarni, \{Girish N.\} and Neale, \{Benjamin M.\} and Nielsen, \{Henriette Svarre\} and Mette Nyegaard and Ostrowski, \{Sisse R.\} and Pedersen, \{Ole B.V.\} and Erik S{\o}rensen and Christina Mikkelsen and Christian Erikstrup and Kaspersen, \{Kathrine A.\} and Bruun, \{Mie T.\} and Bitten Aagaard and Henrik Ullum and Barbara Obermayer-Pietsch and Aarno Palotie and Reeve, \{Mary P.\} and Andres Salumets and Richa Saxena and Spector, \{Timothy D.\} and Stuckey, \{Bronwyn G.A.\} and Unnur Thorsteinsdottir and Uitterlinden, \{Andr{\'e} G.\} and Margrit Urbanek and Sebastian Z{\"o}llner and \{van Heel\}, \{David A.\} and Sayantan Das and Bell, \{Robert K.\} and Tung, \{Joyce Y.\} and Weldon, \{Catherine H.\} and \{van Heel\}, \{David A.\} and Hirschhorn, \{Joel N.\} and Kari Stefansson and Perry, \{John R.B.\} and Unnur Styrkarsdottir and Wilson, \{Scott G.\} and Terhi Piltonen and Triin Laisk and Jarvelin, \{Marjo Riitta\} and Kharis Burns and Justice, \{Anne E.\} and Hannele Laivuori and Ong, \{Ken K.\} and Goodarzi, \{Mark O.\} and Davis, \{Lea K.\} and Andrea Dunaif and Lindgren, \{Cecilia M.\} and Laven, \{Joop S.E.\} and Stephen Franks and Visser, \{Jenny A.\} and Welt, \{Corrine K.\} and Tugce Karaderi and \{Genes and Health Research Team\} and \{DBDS Genomic Consortium\} and \{23andMe Research Team\} and Day, \{Felix R.\}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2026.",

year = "2026",

doi = "10.1038/s41588-026-02543-9",

language = "English",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

}

TY - JOUR

T1 - Genomic analyses implicate hormonal and metabolic dysregulation in polycystic ovary syndrome

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 - Morton, Cynthia

AU - Nadkarni, Girish N.

AU - Neale, Benjamin M.

AU - Nielsen, Henriette Svarre

AU - Nyegaard, Mette

AU - Ostrowski, Sisse R.

AU - Pedersen, Ole B.V.

AU - Sørensen, Erik

AU - Mikkelsen, Christina

AU - Erikstrup, Christian

AU - Kaspersen, Kathrine A.

AU - Bruun, Mie T.

AU - Aagaard, Bitten

AU - Ullum, Henrik

AU - Obermayer-Pietsch, Barbara

AU - Palotie, Aarno

AU - Reeve, Mary P.

AU - Salumets, Andres

AU - Saxena, Richa

AU - Spector, Timothy D.

AU - Stuckey, Bronwyn G.A.

AU - Thorsteinsdottir, Unnur

AU - Uitterlinden, André G.

AU - Urbanek, Margrit

AU - Zöllner, Sebastian

AU - van Heel, David A.

AU - Das, Sayantan

AU - Bell, Robert K.

AU - Tung, Joyce Y.

AU - Weldon, Catherine H.

AU - van Heel, David A.

AU - Hirschhorn, Joel N.

AU - Stefansson, Kari

AU - Perry, John R.B.

AU - Styrkarsdottir, Unnur

AU - Wilson, Scott G.

AU - Piltonen, Terhi

AU - Laisk, Triin

AU - Jarvelin, Marjo Riitta

AU - Burns, Kharis

AU - Justice, Anne E.

AU - Laivuori, Hannele

AU - Ong, Ken K.

AU - Goodarzi, Mark O.

AU - Davis, Lea K.

AU - Dunaif, Andrea

AU - Lindgren, Cecilia M.

AU - Laven, Joop S.E.

AU - Franks, Stephen

AU - Visser, Jenny A.

AU - Welt, Corrine K.

AU - Karaderi, Tugce

AU - Genes and Health Research Team

AU - DBDS Genomic Consortium

AU - 23andMe Research Team

AU - Day, Felix R.

PY - 2026

Y1 - 2026

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 - Journal article

C2 - 42026183

AN - SCOPUS:105036692907

SN - 1061-4036

JO - Nature Genetics

JF - Nature Genetics

ER -

Genomic analyses implicate hormonal and metabolic dysregulation in polycystic ovary syndrome

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