{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T16:25:27Z","timestamp":1787502327237,"version":"build-2736575974"},"reference-count":52,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2015,8,25]],"date-time":"2015-08-25T00:00:00Z","timestamp":1440460800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"DOI":"10.1371\/journal.pgen.1005455","type":"journal-article","created":{"date-parts":[[2015,8,25]],"date-time":"2015-08-25T14:18:26Z","timestamp":1440512306000},"page":"e1005455","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":98,"title":["Systems Genetics Reveals the Functional Context of PCOS Loci and Identifies Genetic and Molecular Mechanisms of Disease Heterogeneity"],"prefix":"10.1371","volume":"11","author":[{"given":"Michelle R.","family":"Jones","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meredith A.","family":"Brower","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinrui","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emebet","family":"Mengesha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yii-Der I.","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kent D.","family":"Taylor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo","family":"Azziz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark O.","family":"Goodarzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2015,8,25]]},"reference":[{"issue":"4","key":"ref1","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1038\/nrendo.2010.217","article-title":"Polycystic ovary syndrome: etiology, pathogenesis and diagnosis","volume":"7","author":"MO Goodarzi","year":"2011","journal-title":"Nat Rev Endocrinol"},{"issue":"12","key":"ref2","doi-asserted-by":"crossref","first-page":"4546","DOI":"10.1210\/jc.2007-1549","article-title":"Glucose intolerance in polycystic ovary syndrome\u2014a position statement of the Androgen Excess Society","volume":"92","author":"KE Salley","year":"2007","journal-title":"J Clin Endocrinol Metab"},{"issue":"6","key":"ref3","doi-asserted-by":"crossref","first-page":"2100","DOI":"10.1210\/jc.2005-1494","article-title":"Heritability of polycystic ovary syndrome in a Dutch twin-family study","volume":"91","author":"JM Vink","year":"2006","journal-title":"J Clin Endocrinol Metab"},{"issue":"1","key":"ref4","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1038\/ng.732","article-title":"Genome-wide association study identifies susceptibility loci for polycystic ovary syndrome on chromosome 2p16.3, 2p21 and 9q33.3","volume":"43","author":"ZJ Chen","year":"2011","journal-title":"Nat Genet"},{"issue":"9","key":"ref5","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1038\/ng.2384","article-title":"Genome-wide association study identifies eight new risk loci for polycystic ovary syndrome","volume":"44","author":"Y Shi","year":"2012","journal-title":"Nat Genet"},{"issue":"2","key":"ref6","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1136\/jmedgenet-2011-100427","article-title":"Replication of association of DENND1A and THADA variants with polycystic ovary syndrome in European cohorts","volume":"49","author":"MO Goodarzi","year":"2012","journal-title":"J Med Genet"},{"issue":"7","key":"ref7","doi-asserted-by":"crossref","first-page":"E1342","DOI":"10.1210\/jc.2011-3478","article-title":"Variants in DENND1A are associated with polycystic ovary syndrome in women of European ancestry","volume":"97","author":"CK Welt","year":"2012","journal-title":"J Clin Endocrinol Metab"},{"issue":"1","key":"ref8","doi-asserted-by":"crossref","first-page":"E185","DOI":"10.1210\/jc.2012-2471","article-title":"Evidence for chromosome 2p16.3 polycystic ovary syndrome susceptibility locus in affected women of European ancestry","volume":"98","author":"P Mutharasan","year":"2013","journal-title":"J Clin Endocrinol Metab"},{"key":"ref9","article-title":"Cross-Ethnic Meta-analysis of Genetic Variants for Polycystic Ovary Syndrome","author":"YV Louwers","year":"2013","journal-title":"J Clin Endocrinol Metab"},{"key":"ref10","first-page":"jc20142689","article-title":"Further Investigation in Europeans of Susceptibility Variants for Polycystic Ovary Syndrome Discovered in Genome-wide Association Studies of Chinese Individuals","author":"MA Brower","year":"2014","journal-title":"J Clin Endocrinol Metab"},{"issue":"11","key":"ref11","doi-asserted-by":"crossref","first-page":"3086","DOI":"10.1093\/humrep\/det352","article-title":"Increased protein expression of LHCG receptor and 17alpha-hydroxylase\/17-20-lyase in human polycystic ovaries","volume":"28","author":"FV Comim","year":"2013","journal-title":"Hum Reprod"},{"issue":"4","key":"ref12","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1210\/en.2013-1764","article-title":"Hypomethylation of the LH\/choriogonadotropin receptor promoter region is a potential mechanism underlying susceptibility to polycystic ovary syndrome","volume":"155","author":"P Wang","year":"2014","journal-title":"Endocrinology"},{"issue":"15","key":"ref13","doi-asserted-by":"crossref","first-page":"E1519","DOI":"10.1073\/pnas.1400574111","article-title":"Overexpression of a DENND1A isoform produces a polycystic ovary syndrome theca phenotype","volume":"111","author":"JM McAllister","year":"2014","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"5","key":"ref14","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1016\/j.ajhg.2013.10.004","article-title":"Global analysis of DNA methylation variation in adipose tissue from twins reveals links to disease-associated variants in distal regulatory elements","volume":"93","author":"E Grundberg","year":"2013","journal-title":"Am J Hum Genet"},{"issue":"7","key":"ref15","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1038\/ng.174","article-title":"Genomic surveys by methylation-sensitive SNP analysis identify sequence-dependent allele-specific DNA methylation","volume":"40","author":"K Kerkel","year":"2008","journal-title":"Nat Genet"},{"issue":"Suppl 5","key":"ref16","first-page":"1291","article-title":"Molecular defects of insulin action in the polycystic ovary syndrome: possible tissue specificity","volume":"13","author":"TP Ciaraldi","year":"2000","journal-title":"J Pediatr Endocrinol Metab"},{"issue":"1","key":"ref17","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1210\/jc.2008-1492","article-title":"Polycystic ovary syndrome is associated with tissue-specific differences in insulin resistance","volume":"94","author":"TP Ciaraldi","year":"2009","journal-title":"J Clin Endocrinol Metab"},{"issue":"9","key":"ref18","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1056\/NEJM198903023200904","article-title":"Pituitary-ovarian responses to nafarelin testing in the polycystic ovary syndrome","volume":"320","author":"RB Barnes","year":"1989","journal-title":"N Engl J Med"},{"issue":"11","key":"ref19","first-page":"3728","article-title":"Inappropriate gonadotropin secretion in polycystic ovary syndrome: influence of adiposity","volume":"82","author":"A Arroyo","year":"1997","journal-title":"J Clin Endocrinol Metab"},{"issue":"5","key":"ref20","doi-asserted-by":"crossref","first-page":"1320","DOI":"10.1172\/JCI108400","article-title":"Characterization of the inappropriate gonadotropin secretion in polycystic ovary syndrome","volume":"57","author":"R Rebar","year":"1976","journal-title":"J Clin Invest"},{"issue":"4","key":"ref21","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1210\/jcem-73-4-811","article-title":"Serum bioactive and immunoreactive luteinizing hormone and follicle-stimulating hormone levels in women with cycle abnormalities, with or without polycystic ovarian disease","volume":"73","author":"BC Fauser","year":"1991","journal-title":"J Clin Endocrinol Metab"},{"issue":"5","key":"ref22","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1016\/S0015-0282(16)47064-0","article-title":"Elevated bioactive luteinizing hormone in women with the polycystic ovary syndrome","volume":"39","author":"RA Lobo","year":"1983","journal-title":"Fertil Steril"},{"issue":"12","key":"ref23","doi-asserted-by":"crossref","first-page":"5925","DOI":"10.1210\/jcem.86.12.8088","article-title":"The biochemical basis for increased testosterone production in theca cells propagated from patients with polycystic ovary syndrome","volume":"86","author":"VL Nelson","year":"2001","journal-title":"J Clin Endocrinol Metab"},{"issue":"4","key":"ref24","first-page":"1158","article-title":"Hypersecretion of androstenedione by isolated thecal cells from polycystic ovaries","volume":"79","author":"C Gilling-Smith","year":"1994","journal-title":"J Clin Endocrinol Metab"},{"key":"ref25","unstructured":"The Genotype-Expression Project 2015 [cited 2015 14 May 2015]. <ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/www.gtexportal.org\" xlink:type=\"simple\">http:\/\/www.gtexportal.org<\/ext-link>."},{"issue":"6","key":"ref26","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1210\/er.2011-1034","article-title":"Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications","volume":"33","author":"E Diamanti-Kandarakis","year":"2012","journal-title":"Endocr Rev"},{"issue":"3","key":"ref27","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1093\/humrep\/des463","article-title":"Women with polycystic ovary syndrome have intrinsic insulin resistance on euglycaemic-hyperinsulaemic clamp","volume":"28","author":"NK Stepto","year":"2013","journal-title":"Hum Reprod"},{"issue":"9","key":"ref28","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.2337\/diab.38.9.1165","article-title":"Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome","volume":"38","author":"A Dunaif","year":"1989","journal-title":"Diabetes"},{"issue":"1","key":"ref29","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1210\/jcem-72-1-83","article-title":"A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syndrome","volume":"72","author":"JE Nestler","year":"1991","journal-title":"J Clin Endocrinol Metab"},{"issue":"6","key":"ref30","first-page":"2001","article-title":"Insulin stimulates testosterone biosynthesis by human thecal cells from women with polycystic ovary syndrome by activating its own receptor and using inositolglycan mediators as the signal transduction system","volume":"83","author":"JE Nestler","year":"1998","journal-title":"J Clin Endocrinol Metab"},{"issue":"1","key":"ref31","doi-asserted-by":"crossref","first-page":"114","DOI":"10.2337\/db11-0956","article-title":"Reproductive tissues maintain insulin sensitivity in diet-induced obesity","volume":"61","author":"S Wu","year":"2012","journal-title":"Diabetes"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"jc00009999","DOI":"10.1210\/jc.0000-9999","article-title":"Adrenal androgen excess and body mass index in polycystic ovary syndrome","author":"C Moran","year":"2015","journal-title":"J Clin Endocrinol Metab"},{"issue":"3","key":"ref33","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1016\/j.cell.2009.02.042","article-title":"Disassembly of exon junction complexes by PYM","volume":"137","author":"NH Gehring","year":"2009","journal-title":"Cell"},{"issue":"12","key":"ref34","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1038\/nsmb1321","article-title":"PYM binds the cytoplasmic exon-junction complex and ribosomes to enhance translation of spliced mRNAs","volume":"14","author":"MD Diem","year":"2007","journal-title":"Nat Struct Mol Biol"},{"issue":"1","key":"ref35","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.bbrc.2007.09.089","article-title":"A role for Rab5 activity in the biogenesis of endosomal and lysosomal compartments","volume":"364","author":"Y Hirota","year":"2007","journal-title":"Biochem Biophys Res Commun"},{"key":"ref36","doi-asserted-by":"crossref","first-page":"D1001","DOI":"10.1093\/nar\/gkt1229","article-title":"The NHGRI GWAS Catalog, a curated resource of SNP-trait associations","volume":"42","author":"D Welter","year":"2014","journal-title":"Nucleic Acids Res"},{"issue":"3","key":"ref37","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1016\/j.molcel.2009.12.037","article-title":"The Connecdenn DENN domain: a GEF for Rab35 mediating cargo-specific exit from early endosomes","volume":"37","author":"PD Allaire","year":"2010","journal-title":"Mol Cell"},{"issue":"5944","key":"ref38","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1126\/science.1176077","article-title":"Eos mediates Foxp3-dependent gene silencing in CD4+ regulatory T cells","volume":"325","author":"F Pan","year":"2009","journal-title":"Science"},{"issue":"1","key":"ref39","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.fertnstert.2011.11.023","article-title":"Is PCOS an inflammatory process?","volume":"97","author":"AJ Duleba","year":"2012","journal-title":"Fertil Steril"},{"issue":"9","key":"ref40","doi-asserted-by":"crossref","first-page":"2043","DOI":"10.1161\/ATVBAHA.107.149484","article-title":"Interleukin-18, the metabolic syndrome, and subclinical atherosclerosis: results from the Dallas Heart Study","volume":"27","author":"A Zirlik","year":"2007","journal-title":"Arterioscler Thromb Vasc Biol"},{"issue":"2","key":"ref41","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1210\/jc.2003-031365","article-title":"Serum interleukin-18 concentrations are increased in the polycystic ovary syndrome: relationship to insulin resistance and to obesity","volume":"89","author":"HF Escobar-Morreale","year":"2004","journal-title":"J Clin Endocrinol Metab"},{"issue":"1","key":"ref42","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1210\/jc.2004-0628","article-title":"The increase of leukocytes as a new putative marker of low-grade chronic inflammation and early cardiovascular risk in polycystic ovary syndrome","volume":"90","author":"F Orio Jr.","year":"2005","journal-title":"J Clin Endocrinol Metab"},{"issue":"6","key":"ref43","doi-asserted-by":"crossref","first-page":"2291","DOI":"10.1016\/j.fertnstert.2007.10.025","article-title":"Adipocytes from women with polycystic ovary syndrome demonstrate altered phosphorylation and activity of glycogen synthase kinase 3","volume":"90","author":"W Chang","year":"2008","journal-title":"Fertil Steril"},{"issue":"2","key":"ref44","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1016\/j.fertnstert.2008.06.035","article-title":"The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report","volume":"91","author":"R Azziz","year":"2009","journal-title":"Fertil Steril"},{"issue":"6","key":"ref45","doi-asserted-by":"crossref","first-page":"2745","DOI":"10.1210\/jc.2003-032046","article-title":"The prevalence and features of the polycystic ovary syndrome in an unselected population","volume":"89","author":"R Azziz","year":"2004","journal-title":"J Clin Endocrinol Metab"},{"issue":"5","key":"ref46","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1038\/ng1547","article-title":"A genome-wide scalable SNP genotyping assay using microarray technology","volume":"37","author":"KL Gunderson","year":"2005","journal-title":"Nat Genet"},{"key":"ref47","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/S0076-6879(06)10017-8","article-title":"Whole-genome genotyping","volume":"410","author":"KL Gunderson","year":"2006","journal-title":"Methods Enzymol"},{"key":"ref48","unstructured":"Davis S DP, Bilke S, Triche T, Jr., Bootwalla M. Methylumi: Handle Illumina Methylation Data. R package version 2.12.02014."},{"key":"ref49","doi-asserted-by":"crossref","DOI":"10.1007\/0-387-29362-0_23","article-title":"Limma: Linear Models for Microarray Data","author":"G Smyth","year":"2005"},{"key":"ref50","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false discovery rate: a practical and powerful approach to multiple testing","author":"Y Benjamini","year":"1995","journal-title":"Journal of the Royal Statistical Society Series B (Methodological)"},{"key":"ref51","doi-asserted-by":"crossref","first-page":"D991","DOI":"10.1093\/nar\/gks1193","article-title":"NCBI GEO: archive for functional genomics data sets\u2014update","volume":"41","author":"T Barrett","year":"2013","journal-title":"Nucleic Acids Res"},{"key":"ref52","doi-asserted-by":"crossref","first-page":"D56","DOI":"10.1093\/nar\/gks1172","article-title":"ENCODE data in the UCSC Genome Browser: year 5 update","volume":"41","author":"KR Rosenbloom","year":"2013","journal-title":"Nucleic Acids Res"}],"container-title":["PLOS Genetics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/dx.plos.org\/10.1371\/journal.pgen.1005455","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,8,29]],"date-time":"2019-08-29T16:40:50Z","timestamp":1567096850000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pgen.1005455"}},"subtitle":[],"editor":[{"given":"Jan M.","family":"McAllister","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2015,8,25]]},"references-count":52,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2015,8,25]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pgen.1005455","relation":{},"ISSN":["1553-7404"],"issn-type":[{"value":"1553-7404","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,8,25]]}}}