University of Oulu

Jia Zhu, Natàlia Pujol-Gualdo, Laura B L Wittemans, Cecilia M Lindgren, Triin Laisk, Joel N Hirschhorn, Yee-Ming Chan, Evidence From Men for Ovary-independent Effects of Genetic Risk Factors for Polycystic Ovary Syndrome, The Journal of Clinical Endocrinology & Metabolism, Volume 107, Issue 4, April 2022, Pages e1577–e1587, https://doi.org/10.1210/clinem/dgab838

Evidence from men for ovary-independent effects of genetic risk factors for polycystic ovary syndrome

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Author: Zhu, Jia1,2,3; Pujol-Gualdo, Natàlia4,5; Wittemans, Laura B. L.6,7;
Organizations: 1Division of Endocrinology, Boston Children’s Hospital, Boston, MA 02115 , USA
2Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
3Department of Pediatrics, Harvard Medical School, Boston, MA 02115 , USA
4Estonian Genome Centre, Institute of Genomics, University of Tartu 51010, Tartu, Estonia
5Department of Obstetrics and Gynecology, PEDEGO Research Unit, Medical Research Centre, Oulu University Hospital, University of Oulu FI-90014, Oulu, Finland
6Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford OX3 ZFZ, UK
7Nuffield Department of Women’s and Reproductive Health, University of Oxford, Oxford OX3 9DU, UK
8The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7FZ, UK
9Division of Endocrinology, Boston Children’s Hospital, Boston, MA 02115, USA
10Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
11Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.9 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2022092860357
Language: English
Published: Endocrine society, 2022
Publish Date: 2022-09-28
Description:

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.

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Series: Journal of clinical endocrinology & metabolism
ISSN: 0021-972X
ISSN-E: 1945-7197
ISSN-L: 0021-972X
Volume: 107
Issue: 4
Pages: e1577 - e1587
DOI: 10.1210/clinem/dgab838
OADOI: https://oadoi.org/10.1210/clinem/dgab838
Type of Publication: A1 Journal article – refereed
Field of Science: 3123 Gynaecology and paediatrics
Subjects:
Funding: J.Z. was supported by grant 5T32DK007699 from the National Institute of Diabetes and Digestive and Kidney Diseases, a Pediatric Endocrine Society Rising Star and Research Fellowship Award, and an Endocrine Fellows Foundation Fellow Grant Award. T.L. is supported by Estonian Research Council grant PRG687. N.P.-G. is supported by MATER Marie Sklodowska-Curie, which received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No. 813707. C.M.L. is supported by the Li Ka Shing Foundation; NIHR Oxford Biomedical Research Centre, Oxford; National Institutes of Health; Gates Foundation; and a Wellcome Trust Investigator Award (221782/Z/20/Z). J.N.H. is supported by grant R01DK075787 from the National Institute of Diabetes and Digestive and Kidney Diseases.
Copyright information: © The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
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