Evidence From Men for Ovary-independent Effects of Genetic Risk Factors for Polycystic Ovary Syndrome

• Published in: The journal of clinical endocrinology and metabolism Vol. 107; no. 4; pp. e1577 - e1587
• Main Authors: Zhu, Jia, Pujol-Gualdo, Natàlia, Wittemans, Laura B L, Lindgren, Cecilia M, Laisk, Triin, Hirschhorn, Joel N, Chan, Yee-Ming
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 24.03.2022
• Subjects: Alopecia; Coronary heart disease; Diabetes Mellitus, Type 2 - complications; Female; Glycosylated hemoglobin; Humans; Mediation; Obesity; Online Only; Polycystic Ovary Syndrome - complications; Polycystic Ovary Syndrome - epidemiology; Polycystic Ovary Syndrome - genetics; Risk Factors; Stein-Leventhal syndrome; Type 2 diabetes; United Kingdom; PCOS; polygenic risk score; obesity; polycystic ovary syndrome
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/clinem/dgab838

Polycystic ovary syndrome (PCOS) is characterized by ovulatory dysfunction and hyperandrogenism and can be associated with cardiometabolic dysfunction, but it remains unclear which of these features are inciting causes and which are secondary consequences. To determine whether ovarian function is necessary for genetic risk factors for PCOS to produce nonreproductive phenotypes. Cohort of 176 360 men in the UK Biobank and replication cohort of 37 348 men in the Estonian Biobank. We calculated individual PCOS polygenic risk scores (PRS), tested for association of these PRS with PCOS-related phenotypes using linear and logistic regression and performed mediation analysis. For every 1 SD increase in the PCOS PRS, men had increased odds of obesity (odds ratio [OR]: 1.09; 95% CI, 1.08-1.10; P = 1 × 10-49), type 2 diabetes mellitus (T2DM) (OR: 1.08; 95% CI, 1.05-1.10; P = 3 × 10-12), coronary artery disease (CAD) (OR: 1.03; 95% CI, 1.01-1.04; P = 0.0029), and marked androgenic alopecia (OR: 1.03; 95% CI, 1.02-1.05; P = 3 × 10-5). Body mass index (BMI), hemoglobin A1c, triglycerides, and free androgen index increased as the PRS increased, whereas high-density lipoprotein cholesterol and SHBG decreased (all P < .0001). The association between the PRS and CAD appeared to be completely mediated by BMI, whereas the associations with T2DM and marked androgenic alopecia appeared to be partially mediated by BMI. Genetic risk factors for PCOS have phenotypic consequences in men, indicating that they can act independently of ovarian function. Thus, PCOS in women may not always be a primary disorder of the ovaries.