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

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cam.issuedOnline2018-12-19
datacite.issupplementedby.urlhttps://doi.org/10.17863/CAM.36024
datacite.issupplementedby.urlhttps://doi.org/10.17863/CAM.27720
dc.contributor.authorDay, Felix
dc.contributor.authorKaraderi, Tugce
dc.contributor.authorJones, Michelle R
dc.contributor.authorMeun, Cindy
dc.contributor.authorHe, Chunyan
dc.contributor.authorDrong, Alex
dc.contributor.authorKraft, Peter
dc.contributor.authorLin, Nan
dc.contributor.authorHuang, Hongyan
dc.contributor.authorBroer, Linda
dc.contributor.authorMagi, Reedik
dc.contributor.authorSaxena, Richa
dc.contributor.authorLaisk, Triin
dc.contributor.authorUrbanek, Margrit
dc.contributor.authorHayes, M Geoffrey
dc.contributor.authorThorleifsson, Gudmar
dc.contributor.authorFernandez-Tajes, Juan
dc.contributor.authorMahajan, Anubha
dc.contributor.authorMullin, Benjamin H
dc.contributor.authorStuckey, Bronwyn GA
dc.contributor.authorSpector, Timothy D
dc.contributor.authorWilson, Scott G
dc.contributor.authorGoodarzi, Mark O
dc.contributor.authorDavis, Lea
dc.contributor.authorObermayer-Pietsch, Barbara
dc.contributor.authorUitterlinden, André G
dc.contributor.authorAnttila, Verneri
dc.contributor.authorNeale, Benjamin M
dc.contributor.authorJarvelin, Marjo-Riitta
dc.contributor.authorFauser, Bart
dc.contributor.authorKowalska, Irina
dc.contributor.authorVisser, Jenny A
dc.contributor.authorAndersen, Marianne
dc.contributor.authorOng, Ken
dc.contributor.authorStener-Victorin, Elisabet
dc.contributor.authorEhrmann, David
dc.contributor.authorLegro, Richard S
dc.contributor.authorSalumets, Andres
dc.contributor.authorMcCarthy, Mark I
dc.contributor.authorMorin-Papunen, Laure
dc.contributor.authorThorsteinsdottir, Unnur
dc.contributor.authorStefansson, Kari
dc.contributor.author23andMe Research Team
dc.contributor.authorStyrkarsdottir, Unnur
dc.contributor.authorPerry, John RB
dc.contributor.authorDunaif, Andrea
dc.contributor.authorLaven, Joop
dc.contributor.authorFranks, Steve
dc.contributor.authorLindgren, Cecilia M
dc.contributor.authorWelt, Corrine K
dc.contributor.orcidDay, Felix [0000-0003-3789-7651]
dc.contributor.orcidOng, Kenneth [0000-0003-4689-7530]
dc.contributor.orcidPerry, John [0000-0001-6483-3771]
dc.date.accessioned2019-02-06T11:27:19Z
dc.date.available2019-02-06T11:27:19Z
dc.date.issued2018-12-19
dc.description.abstractPolycystic 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.
dc.identifier.doi10.17863/CAM.36095
dc.identifier.eissn1553-7404
dc.identifier.issn1553-7390
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/288832
dc.languageeng
dc.language.isoeng
dc.publisherPublic Library of Science (PLoS)
dc.publisher.urlhttps://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1007813
dc.rightsAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectAsian People
dc.subjectCase-Control Studies
dc.subjectCohort Studies
dc.subjectFemale
dc.subjectGenetic Predisposition to Disease
dc.subjectGenome-Wide Association Study
dc.subjectHumans
dc.subjectPhenotype
dc.subjectPolycystic Ovary Syndrome
dc.subjectWhite People
dc.titleLarge-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria.
dc.typeArticle
dcterms.dateAccepted2018-11-06
prism.endingPagee1007813
prism.issueIdentifier12
prism.publicationDate2018
prism.publicationNamePLoS Genetics
prism.startingPagee1007813
prism.volume14
pubs.funder-project-idMedical Research Council (MC_UU_12015/2)
pubs.funder-project-idMedical Research Council (MC_U106179472)
rioxxterms.licenseref.startdate2018-12-19
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1371/journal.pgen.1007813

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