{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T21:00:38Z","timestamp":1792616438749,"version":"4.5.0"},"reference-count":58,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,2,26]],"date-time":"2024-02-26T00:00:00Z","timestamp":1708905600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,2,26]],"date-time":"2024-02-26T00:00:00Z","timestamp":1708905600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Genomics"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Polycystic ovary syndrome (PCOS) is a complex multifactorial disorder with a substantial genetic component. However, the clinical manifestations of PCOS are heterogeneous with notable differences between lean and obese women, implying a different pathophysiology manifesting in differential body mass index (BMI). We performed a meta-analysis of genome-wide association study (GWAS) data from six well-characterised cohorts, using a case\u2013control study design stratified by BMI, aiming to identify genetic variants associated with lean and overweight\/obese PCOS subtypes.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>The study comprised 254,588 women (5,937 cases and 248,651 controls) from individual studies performed in Australia, Estonia, Finland, the Netherlands and United States of America, and separated according to three BMI stratifications (lean, overweight and obese). Genome-wide association analyses were performed for each stratification within each cohort, with the data for each BMI group meta-analysed using METAL software. Almost half of the total study population (47%, <jats:italic>n<\/jats:italic>\u2009=\u2009119,584) were of lean BMI (\u2264\u200925\u00a0kg\/m<jats:sup>2<\/jats:sup>). Two genome-wide significant loci were identified for lean PCOS, led by rs12000707 within <jats:italic>DENND1A<\/jats:italic> (<jats:italic>P<\/jats:italic>\u2009=\u20091.55\u2009\u00d7\u200910<jats:sup>\u201312<\/jats:sup>) and rs2228260 within <jats:italic>XBP1<\/jats:italic> (<jats:italic>P<\/jats:italic>\u2009=\u20093.68\u2009\u00d7\u200910<jats:sup>\u20138<\/jats:sup>). One additional locus, <jats:italic>LINC02905<\/jats:italic>, was highlighted as significantly associated with lean PCOS through gene-based analyses (<jats:italic>P<\/jats:italic>\u2009=\u20091.76\u2009\u00d7\u200910<jats:sup>\u20136<\/jats:sup>). There were no significant loci observed for the overweight or obese sub-strata when analysed separately, however, when these strata were combined, an association signal led by rs569675099 within <jats:italic>DENND1A<\/jats:italic> reached genome-wide significance (<jats:italic>P<\/jats:italic>\u2009=\u20093.22\u2009\u00d7\u200910<jats:sup>\u20139<\/jats:sup>) and a gene-based association was identified with <jats:italic>ERBB4<\/jats:italic> (<jats:italic>P<\/jats:italic>\u2009=\u20091.59\u2009\u00d7\u200910<jats:sup>\u20136<\/jats:sup>). Nineteen of 28 signals identified in previous GWAS, were replicated with consistent allelic effect in the lean stratum. There were less replicated signals in the overweight and obese groups, and only 4 SNPs were replicated in each of the three BMI strata.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Genetic variation at the <jats:italic>XBP1, LINC02905<\/jats:italic> and <jats:italic>ERBB4<\/jats:italic> loci were associated with PCOS within unique BMI strata, while <jats:italic>DENND1A<\/jats:italic> demonstrated associations across multiple strata, providing evidence of both distinct and shared genetic features between lean and overweight\/obese PCOS-affected women. This study demonstrated that PCOS-affected women with contrasting body weight are not only phenotypically distinct but also show variation in genetic architecture; lean PCOS women typically display elevated gonadotrophin ratios, lower insulin resistance, higher androgen levels, including adrenal androgens, and more favourable lipid profiles. Overall, these findings add to the growing body of evidence supporting a genetic basis for PCOS as well as differences in genetic patterns relevant to PCOS BMI-subtype.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12864-024-09990-w","type":"journal-article","created":{"date-parts":[[2024,2,26]],"date-time":"2024-02-26T09:02:34Z","timestamp":1708938154000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Body mass index stratified meta-analysis of genome-wide association studies of polycystic ovary syndrome in women of European ancestry"],"prefix":"10.1186","volume":"25","author":[{"given":"Kharis","family":"Burns","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin H.","family":"Mullin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Loes M. 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Written informed consent was obtained from all participants. BioVU \u2013 Approved by the Institutional Review Board at Vanderbilt University (#160279).WA-PCOS by the SCGOPHCG Human Research Ethics Committee (RGS0000001467) and controls by HRA North West \u2013 Liverpool East Research Ethics Committee (19\/NW\/0187; TwinsUK).-Estonian Biobank\u2014All biobank participants have signed a broad informed consent form and analyses were carried out under ethical approval 1.1\u201312\/624 from the Estonian Committee on Bioethics and Human Research (Estonian Ministry of Social Affairs) and data release N05 from the EstBB.-FinnGen\u2014Patients and control subjects in FinnGen provided informed consent for biobank research, based on the Finnish Biobank Act. Alternatively, separate research cohorts, collected prior the Finnish Biobank Act came into effect (in September 2013) and start of FinnGen (August 2017), were collected based on study-specific consents and later transferred to the Finnish biobanks after approval by Fimea (Finnish Medicines Agency), the National Supervisory Authority for Welfare and Health. Recruitment protocols followed the biobank protocols approved by Fimea. The Coordinating Ethics Committee of the Hospital District of Helsinki and Uusimaa (HUS) statement number for the FinnGen study is Nr HUS\/990\/2017.The FinnGen study is approved by Finnish Institute for Health and Welfare (permit numbers: THL\/2031\/6.02.00\/2017, THL\/1101\/5.05.00\/2017, THL\/341\/6.02.00\/2018, THL\/2222\/6.02.00\/2018, THL\/283\/6.02.00\/2019, THL\/1721\/5.05.00\/2019 and THL\/1524\/5.05.00\/2020), Digital and population data service agency (permit numbers: VRK43431\/2017\u20133, VRK\/6909\/2018\u20133, VRK\/4415\/2019\u20133), the Social Insurance Institution (permit numbers: KELA 58\/522\/2017, KELA 131\/522\/2018, KELA 70\/522\/2019, KELA 98\/522\/2019, KELA 134\/522\/2019, KELA 138\/522\/2019, KELA 2\/522\/2020, KELA 16\/522\/2020), Findata permit numbers THL\/2364\/14.02\/2020, THL\/4055\/14.06.00\/2020,,THL\/3433\/14.06.00\/2020, THL\/4432\/14.06\/2020, THL\/5189\/14.06\/2020, THL\/5894\/14.06.00\/2020, THL\/6619\/14.06.00\/2020, THL\/209\/14.06.00\/2021, THL\/688\/14.06.00\/2021, THL\/1284\/14.06.00\/2021, THL\/1965\/14.06.00\/2021, THL\/5546\/14.02.00\/2020 and Statistics Finland (permit numbers: TK-53\u20131041-17 and TK\/143\/07.03.00\/2020 (earlier TK-53\u201390-20)).The Biobank Access Decisions for FinnGen samples and data utilized in FinnGen Data Freeze 7 include: THL Biobank BB2017_55, BB2017_111, BB2018_19, BB_2018_34, BB_2018_67, BB2018_71, BB2019_7, BB2019_8, BB2019_26, BB2020_1, Finnish Red Cross Blood Service Biobank 7.12.2017, Helsinki Biobank HUS\/359\/2017, Auria Biobank AB17-5154 and amendment #1 (August 17 2020), Biobank Borealis of Northern Finland_2017_1013, Biobank of Eastern Finland 1186\/2018 and amendment 22 \u00a7 \/2020, Finnish Clinical Biobank Tampere MH0004 and amendments (21.02.2020 & 06.10.2020), Central Finland Biobank 1\u20132017, and Terveystalo Biobank STB 2018001.- Rotterdam\u2014The Rotterdam PCOS cohort, was approved by institutional review board (Medical Ethics Committee) of the Erasmus Medical Center (04\u2013263).Controls from the Lifelines Cohort Study have been approved by the UMCG Medical ethical committee under number 2007\/152.All methods were carried out in accordance with relevant guidelines and regulations.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The FinnGen project is funded by the following industry partners: AbbVie Inc., AstraZeneca UK Ltd, Biogen MA Inc., Bristol Myers Squibb (and Celgene Corporation & Celgene International II Sarl), Genentech Inc., Merck Sharp & Dohme Corp., Pfizer Inc., GlaxoSmithKline Intellectual Property Development Ltd., Sanofi US Services Inc., Maze Therapeutics Inc., Janssen Biotech Inc, Novartis AG, and Boehringer Ingelheim International GmbH. All other authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"208"}}