University of Oulu

Day F, Karaderi T, Jones MR, Meun C, He C, Drong A, et al. (2018) Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria. PLoS Genet 14(12): e1007813.

Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria

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Author: Day, Felix1; Karaderi, Tugce2,3; Jones, Michelle R.4;
Organizations: 1Univ Cambridge, Sch Clin Med, MRC Epidemiol Unit, Cambridge Biomed Campus, Cambridge, England.
2Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.
3Eastern Mediterranean Univ, Fac Arts & Sci, Dept Biol Sci, Gazimagusa, Cyprus.
4Cedars Sinai Med Ctr, Dept Biomed Sci, Ctr Bioinformat & Funct Genom, Los Angeles, CA 90048 USA.
5Univ Med Ctr Rotterdam, Erasmus MC, Dept Obstet & Gynaecol, Div Reprod Endocrinol & Infertil, Rotterdam, Netherlands.
6Univ Kentucky, Coll Med, Dept Internal Med, Lexington, KY USA.
7Univ Kentucky, Markey Canc Ctr, Lexington, KY USA.
8Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA.
9Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA.
10Univ Med Ctr Rotterdam, Erasmus MC, Dept Internal Med, Rotterdam, Netherlands.
11Univ Tartu, Inst Genom, Estonian Genome Ctr, Tartu, Estonia.
12Harvard Med Sch, Broad Inst Harvard & MIT & Massachusetts Gen Hosp, Boston, MA 02115 USA.
13Univ Tartu, Inst Clin Med, Dept Obstet & Gynaecol, Tartu, Estonia.
14Northwestern Univ, Dept Med, Feinberg Sch Med, Div Endocrinol Metab & Mol Med, Chicago, IL 60611 USA.
15Northwestern Univ, Feinberg Sch Med, Ctr Genet Med, Chicago, IL 60611 USA.
16Northwestern Univ, Dept Anthropol, Evanston, IL 60208 USA.
17Amgen Inc, DeCODE Genet, Reykjavik, Iceland.
18Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.
19Sir Charles Gairdner Hosp, Dept Endocrinol & Diabet, Nedlands, WA, Australia.
20Univ Western Australia, Sch Med & Pharmacol, Crawley, WA, Australia.
21Keogh Inst Med Res, Nedlands, WA, Australia.
22Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England.
23Cedars Sinai Med Ctr, Dept Med, Div Endocrinol Diabet & Metab, Los Angeles, CA 90048 USA.
24Vanderbilt Univ, Med Ctr, Dept Med, Div Med Genet, Nashville, TN USA.
25Vanderbilt Univ, Med Ctr, Vanderbilt Genom Inst, Nashville, TN USA.
26Med Univ Graz, Dept Internal Med, Div Endocrinol & Diabetol, Graz, Austria.
27Broad Inst MIT & Harvard, Stanley Ctr Psychiat Genet, Cambridge, MA USA.
28Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA.
29Harvard Med Sch, Boston, MA USA.
30Imperial Coll London, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, Dept Epidemiol & Biostat, London, England.
31Univ Oulu, Fac Med, Ctr Life Course Hlth Res, Oulu, Finland.
32Univ Oulu, Bioctr Oulu, Oulu, Finland.
33Oulu Univ Hosp, Unit Primary Care, Oulu, Finland.
34Univ Med Ctr, Dept Reprod Med & Gynaecol, Utrecht, Netherlands.
35Med Univ Bialystok, Dept Internal Med & Metab Dis, Bialystok, Poland.
36Univ Med Ctr Rotterdam, Erasmus MC, Endocrinol Sect, Dept Internal Med, Rotterdam, Netherlands.
37Univ Southern Denmark, Odense Univ Hosp, Odense, Denmark.
38Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden.
39Univ Chicago, Dept Med, Sect Adult & Paediat Endocrinol, 5841 S Maryland Ave, Chicago, IL 60637 USA.
40Penn State Univ, Coll Med, Dept Obstet & Gynecol & Publ Hlth Sci, Hershey, PA USA.
41Competence Ctr Hlth Technol, Tartu, Estonia.
42Univ Tartu, Inst Bio & Translat Med, Tartu, Estonia.
43Univ Helsinki, Dept Obstet & Gynecol, Helsinki, Finland.
44Helsinki Univ Hosp, Helsinki, Finland.
45Churchill Hosp, Oxford NIHR Biomed Res Ctr, Oxford, England.
46Univ Oulu, Dept Obstet & Gynecol, Oulu, Finland.
47Oulu Univ Hosp, Med Res Ctr, PEDEGO Res Unit, Oulu, Finland.
48Univ Iceland, Fac Med, Reykjavik, Iceland.
49Icahn Sch Med Mt Sinai, Div Endocrinol Diabet & Bone Dis, New York, NY 10029 USA.
50Imperial Coll London, Dept Surg & Canc, Inst Reprod & Dev Biol, London, England.
51Univ Oxford, Nuffield Dept Med, Big Data Inst, Li Ka Shing Ctr Hlth Informat & Discovery, Oxford, England.
52Univ Utah, Div Endocrinol Metab & Diabet, Salt Lake City, UT 84112 USA.
53Massachusetts Gen Hosp, Reprod Endocrine Unit, Boston, MA 02114 USA.
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.6 MB)
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Language: English
Published: Public Library of Science, 2018
Publish Date: 2021-03-25


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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Series: PLoS genetics
ISSN: 1553-7390
ISSN-E: 1553-7404
ISSN-L: 1553-7390
Volume: 14
Issue: 12
Article number: e1007813
DOI: 10.1371/journal.pgen.1007813
Type of Publication: A1 Journal article – refereed
Field of Science: 3123 Gynaecology and paediatrics
3142 Public health care science, environmental and occupational health
Funding: This work has been supported by MRC grant MC_U106179472 (FD, KO, JRBP), Samuel Oschin Comprehensive Cancer Institute Developmental Funds, Center for Bioinformatics and Functional Genomics and Department of Biomedical Sciences Developmental Funds (MRJ), NCI P30CA177558 (CH), NCI UM1CA186107 (PK), European Regional Development Fund (Project No. 2014-2020.4.01.15-0012) and the European Union’s Horizon 2020 research and innovation program under grant agreements No 692065 (TL, RM, AS) and 692145 (RM), NICHD R01HD065029 (RS), Estonian Ministry of Education and Research (grant IUT34-16 to TL), NICHD R01HD057450 (MU), NICHD P50HD044405 (AD), NICHD R01HD057223 (AD), R01HD085227 (MGH, AD), deCode Genetics (GT, UT, KS, US), Raine Medical Research Foundation Priming Grant (BHM), SCGOPHCG RAC 2015-16/034 (SGW, BGAS), 2016-17/018 (BGAS), NIHR BRC, Wellcome Trust, MRC (TDS), Eris M. Field Chair in Diabetes Research (MOG), NIDDK P30 DK063491 (MOG), NIDDK U01DK094431, U01DK048381 (DE), NICHD U10HD38992 (RL), Estonian Ministry of Education and Research (grant IUT34-16), Enterprise Estonia (grant EU48695); the EU-FP7 Marie Curie Industry-Academia Partnerships and Pathways (IAPP, grant SARM, EU324509 to AS), Wellcome (090532, 098381, 203141); European Commission (ENGAGE: HEALTH-F4-2007-201413 to MIM), MRC G0802782, MR/M012638/1 (SF), Li Ka Shing Foundation, WT-SSI/John Fell Funds, NIHR Biomedical Research Centre, Oxford, Widenlife and NICHD 5P50HD028138-27 (CML), NICHD R01HD065029, ADA 1-10-CT-57, Harvard Clinical and Translational Science Center, from the National Center for Research Resources 1UL1 RR025758 (CKW). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Copyright information: © 2018 Day et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.