Evidence From Men for Ovary-independent Effects of Genetic Risk Factors for Polycystic Ovary Syndrome
Year: 2021
Type: article
Study design: Observational Study
Abstract: CONTEXT: 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. OBJECTIVE: To determine whether ovarian function is necessary for genetic risk factors for PCOS to produce nonreproductive phenotypes. DESIGN, SETTING, AND PARTICIPANTS: Cohort of 176 360 men in the UK Biobank and replication cohort of 37 348 men in the Estonian Biobank. MAIN OUTCOME MEASURES: 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. RESULTS: 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. CONCLUSIONS: 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.
Language: English
Subfield: Reproductive Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,000
Funders: Bill and Melinda Gates Foundation, Li Ka Shing Foundation, Wellcome Trust, Pediatric Endocrine Society, Endocrine Fellows Foundation, National Institute for Health and Care Research, Marie Curie, European Commission, Eesti Teadusagentuur, National Institutes of Health, Medical Research Council, NIHR Oxford Biomedical Research Centre, National Institute of Diabetes and Digestive and Kidney Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G168000094, G2479913792, G2675279392, G3038834426, The molecular aetiology of central obesity: moving from variant to function using large-scale data-driven approaches., G3960264523, G434337789, Dissecting PCOS Physiology by Defining Phenotypes Associated with PCOS Genetic Risk Factors in Men and Children, Development and application of genetic risk prediction algorithms for personalised healthcare in the era of large-scale genomics, Innovative Training Network in Female Reproductive Care, The molecular aetiology of central obesity: moving from variant to function using large-scale data-driven approaches., G5489169023, G5850737185, G9000092240, Biological Insights from Genetic Investigation of ANthropometric Traits (GIANT) Across the Allelic Spectrum
OpenAlex ID: W4205979702