PMID- 34969092 OWN - NLM STAT- MEDLINE DCOM- 20220415 LR - 20240207 IS - 1945-7197 (Electronic) IS - 0021-972X (Print) IS - 0021-972X (Linking) VI - 107 IP - 4 DP - 2022 Mar 24 TI - Evidence From Men for Ovary-independent Effects of Genetic Risk Factors for Polycystic Ovary Syndrome. PG - e1577-e1587 LID - 10.1210/clinem/dgab838 [doi] AB - 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 x 10-49), type 2 diabetes mellitus (T2DM) (OR: 1.08; 95% CI, 1.05-1.10; P = 3 x 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 x 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. CI - (c) The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. FAU - Zhu, Jia AU - Zhu J AUID- ORCID: 0000-0002-8782-1818 AD - Division of Endocrinology, Boston Children's Hospital, Boston, MA 02115, USA. AD - Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. AD - Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA. FAU - Pujol-Gualdo, Natalia AU - Pujol-Gualdo N AD - Estonian Genome Centre, Institute of Genomics, University of Tartu 51010, Tartu, Estonia. AD - Department of Obstetrics and Gynecology, PEDEGO Research Unit, Medical Research Centre, Oulu University Hospital, University of Oulu FI-90014, Oulu, Finland. FAU - Wittemans, Laura B L AU - Wittemans LBL AD - Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford OX3 ZFZ, UK. AD - Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford OX3 9DU, UK. FAU - Lindgren, Cecilia M AU - Lindgren CM AD - Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. AD - Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford OX3 9DU, UK. AD - The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7FZ, UK. FAU - Laisk, Triin AU - Laisk T AUID- ORCID: 0000-0003-1501-9030 AD - Estonian Genome Centre, Institute of Genomics, University of Tartu 51010, Tartu, Estonia. FAU - Hirschhorn, Joel N AU - Hirschhorn JN AD - Division of Endocrinology, Boston Children's Hospital, Boston, MA 02115, USA. AD - Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. AD - Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA. AD - Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. FAU - Chan, Yee-Ming AU - Chan YM AD - Division of Endocrinology, Boston Children's Hospital, Boston, MA 02115, USA. AD - Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. AD - Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA. LA - eng GR - MC_PC_17228/MRC_/Medical Research Council/United Kingdom GR - DH_/Department of Health/United Kingdom GR - F32 HD103317/HD/NICHD NIH HHS/United States GR - WT_/Wellcome Trust/United Kingdom GR - T32 DK007699/DK/NIDDK NIH HHS/United States GR - 813707/MCCC_/Marie Curie/United Kingdom GR - MC_QA137853/MRC_/Medical Research Council/United Kingdom GR - P50 HD104224/HD/NICHD NIH HHS/United States GR - 221782/Z/20/Z/WT_/Wellcome Trust/United Kingdom GR - R01DK075787/DK/NIDDK NIH HHS/United States GR - R01 DK075787/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - J Clin Endocrinol Metab JT - The Journal of clinical endocrinology and metabolism JID - 0375362 SB - IM CIN - J Clin Endocrinol Metab. 2022 Apr 19;107(5):e2188-e2189. PMID: 34905059 CIN - Nat Rev Endocrinol. 2022 Apr;18(4):197-198. PMID: 35149849 MH - Alopecia MH - *Diabetes Mellitus, Type 2/complications MH - Female MH - Humans MH - *Polycystic Ovary Syndrome/complications/epidemiology/genetics MH - Risk Factors PMC - PMC8947237 OTO - NOTNLM OT - PCOS OT - obesity OT - polycystic ovary syndrome OT - polygenic risk score EDAT- 2021/12/31 06:00 MHDA- 2022/04/16 06:00 PMCR- 2021/11/19 CRDT- 2021/12/30 20:33 PHST- 2021/06/12 00:00 [received] PHST- 2021/11/01 00:00 [revised] PHST- 2021/12/31 06:00 [pubmed] PHST- 2022/04/16 06:00 [medline] PHST- 2021/12/30 20:33 [entrez] PHST- 2021/11/19 00:00 [pmc-release] AID - 6432124 [pii] AID - dgab838 [pii] AID - 10.1210/clinem/dgab838 [doi] PST - ppublish SO - J Clin Endocrinol Metab. 2022 Mar 24;107(4):e1577-e1587. doi: 10.1210/clinem/dgab838.