Journal
PLOS GENETICS
Volume 14, Issue 12, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1007813
Keywords
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Categories
Funding
- MRC [MC_U106179472, G0802782, MR/M012638/1]
- Samuel Oschin Comprehensive Cancer Institute Developmental Funds
- Center for Bioinformatics and Functional Genomics
- Department of Biomedical Sciences Developmental Funds
- NCI [P30CA177558, UM1CA186107]
- European Regional Development Fund [2014-2020.4.01.15-0012]
- European Union's Horizon 2020 research and innovation program [692065, 692145]
- NICHD [R01HD065029, R01HD057450, P50HD044405, R01HD057223, R01HD085227, U10HD38992, 5P50HD028138-27]
- Estonian Ministry of Education and Research [IUT34-16]
- deCode Genetics
- Raine Medical Research Foundation Priming Grant
- SCGOPHCG RAC [2015-16/034, 2016-17/018]
- NIHR BRC, Wellcome Trust, MRC
- Eris M. Field Chair in Diabetes Research
- NIDDK [P30 DK063491, U01DK094431, U01DK048381]
- Enterprise Estonia [EU48695]
- EU-FP7 Marie Curie Industry-Academia Partnerships and Pathways (IAPP) [EU324509]
- Wellcome [090532, 098381, 203141]
- European Commission [ENGAGE: HEALTH-F4-2007-201413]
- Li Ka Shing Foundation
- WT-SSI/John Fell Funds
- NIHR Biomedical Research Centre, Oxford
- Widenlife
- Harvard Clinical and Translational Science Center, from the National Center for Research Resources [NICHD R01HD065029, ADA 1-10-CT-57, 1UL1 RR025758]
- Medical Research Council [G0802782, MR/M012638/1, 1241993] Funding Source: researchfish
- MRC [G0802782, MR/N015355/1, MC_UU_12015/2, MR/M012638/1] Funding Source: UKRI
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Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. Affected women frequently have metabolic disturbances including insulin resistance and dysregulation of glucose homeostasis. PCOS is diagnosed with two different sets of diagnostic criteria, resulting in a phenotypic spectrum of PCOS cases. The genetic similarities between cases diagnosed based on the two criteria have been largely unknown. Previous studies in Chinese and European subjects have identified 16 loci associated with risk of PCOS. We report a fixed-effect, inverse-weighted-variance meta-analysis from 10,074 PCOS cases and 103,164 controls of European ancestry and characterisation of PCOS related traits. We identified 3 novel loci (near PLGRKT, ZBTB16 and MAPRE1), and provide replication of 11 previously reported loci. Only one locus differed significantly in its association by diagnostic criteria; otherwise the genetic architecture was similar between PCOS diagnosed by self-report and PCOS diagnosed by NIH or non-NIH Rotterdam criteria across common variants at 13 loci. Identified variants were associated with hyperandrogenism, gonadotropin regulation and testosterone levels in affected women. Linkage disequilibrium score regression analysis revealed genetic correlations with obesity, fasting insulin, type 2 diabetes, lipid levels and coronary artery disease, indicating shared genetic architecture between metabolic traits and PCOS. Mendelian randomization analyses suggested variants associated with body mass index, fasting insulin, menopause timing, depression and male-pattern balding play a causal role in PCOS. The data thus demonstrate 3 novel loci associated with PCOS and similar genetic architecture for all diagnostic criteria. The data also provide the first genetic evidence for a male phenotype for PCOS and a causal link to depression, a previously hypothesized comorbid disease. Thus, the genetics provide a comprehensive view of PCOS that encompasses multiple diagnostic criteria, gender, reproductive potential and mental health.
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