Genomic and proteomic evidence for hormonal and metabolic foundations of 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 Westergard; Jaakko S. Tyrmi; Guðmar Þorleifsson; Yanfei Zhang; Laura B. L. Wittemans; Amber A DeVries; Kelly Brewer; Ryan K. 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

doi:10.1101/2024.04.18.24306020

Genetic & Genomic MedicinemedRxivApr 18, 2024

Preprint

Genomic and proteomic evidence for hormonal and metabolic foundations of polycystic ovary syndrome

Loes M E Moolhuijsen iD, Jia Zhu iD, Benjamin H. Mullin iD, Natàlia Pujol‐Gualdo iD, Ky’Era V. Actkins iD, Jasmine A. Mack iD, Hridya Rao iD, Bhavi Trivedi, Katherine A. Kentistou iD, Yajie Zhao iD, David Westergard, Jaakko S. Tyrmi iD, Guðmar Þorleifsson iD, Yanfei Zhang iD, Laura B. L. Wittemans iD, Amber A DeVries iD, Kelly Brewer iD, Ryan K. Sisk iD, Rebecca Danning, Michael H Preuss iD, Michelle R. Jones iD, Katherine S. Ruth iD, Marianne Andersen iD, Ricardo Azziz iD, Karina Banasik iD, , Felix R. Day iD

Abstract

Polycystic ovary syndrome (PCOS) and its underlying features remain poorly understood. In this genetic and proteomic study, we expand the number of genetic loci from 19 to 29, and identify 31 associated plasma proteins. Many risk-increasing loci were associated with later age at menopause, underscoring the reproductive longevity related to a larger functional ovarian reserve. Hormonal regulation in the aetiology of this condition, through metabolic and reproductive features, was emphasised. The proteomic analysis highlighted perturbations of metabolically-related biology that are typical in women with PCOS. A PCOS polygenic risk score was associated with adverse cardio-metabolic outcomes, with differing contributions of testosterone and BMI in women and men. Finally, while oligo- and anovulatory infertility are characteristic 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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