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Body mass index stratified meta-analysis of genome-wide association studies of polycystic ovary syndrome in women of European ancestry

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  • معلومة اضافية
    • Contributors:
      HUS Gynecology and Obstetrics; Genomics of Neurological and Neuropsychiatric Disorders; Institute for Molecular Medicine Finland; Department of Medical and Clinical Genetics; Department of Obstetrics and Gynecology; Helsinki Institute of Life Science HiLIFE
    • بيانات النشر:
      BMC
    • الموضوع:
      2024
    • Collection:
      Helsingfors Universitet: HELDA – Helsingin yliopiston digitaalinen arkisto
    • نبذة مختصرة :
      Background: 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–control study design stratified by BMI, aiming to identify genetic variants associated with lean and overweight/obese PCOS subtypes. Results: 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%, n = 119,584) were of lean BMI (≤ 25 kg/m2). Two genome-wide significant loci were identified for lean PCOS, led by rs12000707 within DENND1A (P = 1.55 × 10–12) and rs2228260 within XBP1 (P = 3.68 × 10–8). One additional locus, LINC02905, was highlighted as significantly associated with lean PCOS through gene-based analyses (P = 1.76 × 10–6). 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 DENND1A reached genome-wide significance (P = 3.22 × 10–9) and a gene-based association was identified with ERBB4 (P = 1.59 × 10–6). 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. Conclusions: Genetic variation at the XBP1, LINC02905 ...
    • File Description:
      application/pdf
    • Relation:
      The Estonian Biobank work was supported by the Estonian Research council grant PRG1911 and by European Union through the European Regional Development Fund Project No. 2014–2020.4.01.15–0012 GENTRANSMED. WA-PCOS—This study was supported by a grant from the Sir Charles Gairdner Osborne Park Health Care Group Research Advisory Committee, (Grant number: RAC2019-20/029) and, in part, by funding from the National Health and Medical Research Council of Australia (APP2003629 to B.H.M) and a Department of Health (Western Australia) Merit Award (No. 1186046 to B.H.M). BioVU—N/A This study presents independent research supported by the Sir Charles Gairdner Osborne Park Health Care Group, Department of Health (Western Australia), the National Health and Medical Research Council of Australia, Health National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London and the IoPPN Genomics & Biomarker Core Facility, King’s College London. The views expressed are those of the author(s) and not necessarily those of the organisations listed. Estonian Biobank—Data analysis was carried out in part in the High-Performance Computing Center of University of Tartu – FinnGen—We want to acknowledge the participants and investigators of FinnGen study. Following biobanks are acknowledged for delivering biobank samples to FinnGen: Auria Biobank (www.auria.fi/biopankki), THL Biobank (www.thl.fi/biobank), Helsinki Biobank (www.helsinginbiopankki.fi), Biobank Borealis of Northern Finland (https://www.ppshp.fi/Tutkimus-ja-opetus/Biopankki/Pages/Biobank-Borealis-briefly-in-English.aspx), Finnish Clinical Biobank Tampere (www.tays.fi/en-US/Research_and_development/Finnish_Clinical_Biobank_Tampere), Biobank of Eastern Finland (www.ita-suomenbiopankki.fi/en), Central Finland Biobank (www.ksshp.fi/fi-FI/Potilaalle/Biopankki), Finnish Red Cross Blood Service Biobank (www.veripalvelu.fi/verenluovutus/biopankkitoiminta), Terveystalo Biobank (www.terveystalo.com/fi/Yritystietoa/Terveystalo-Biopankki/Biopankki/) and Arctic Biobank (https://www.oulu.fi/en/university/faculties-and-units/faculty-medicine/northern-finland-birth-cohorts-and-arctic-biobank). All Finnish Biobanks are members of BBMRI.fi infrastructure (www.bbmri.fi). Finnish Biobank Cooperative -FINBB (https://finbb.fi/) is the coordinator of BBMRI-ERIC operations in Finland. The Finnish biobank data can be accessed through the Fingenious® services (https://site.fingenious.fi/en/) managed by FINBB. Lifelines Cohort Study—Lifelines is a multi-disciplinary prospective population-based cohort study examining in a unique three-generation design the health and health-related behaviours of 167,729 persons living in the North of the Netherlands. It employs a broad range of investigative procedures in assessing the biomedical, socio-demographic, behavioural, physical and psychological factors which contribute to the health and disease of the general population, with a special focus on multi-morbidity and complex genetics. Consortium name Estonian Biobank Research Team: Andres Metspalu1, Lili Milani1, Tõnu Esko1, Mari Nelis1, Georgi Hudjashov.1 Estonian Biobank Research Team Affiliations. 1Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia, FinnGen: See attached Supplementary Table 6 for 2023 FinnGenn Banner Authors. International PCOS Consortium: Felix R. Day1 Tugce Karaderi2,3 Michelle R. Jones4 Cindy Meun5 Chunyan He6,7 Alex Drong2 Peter Kraft8 Nan Lin6,7 Hongyan Huang8 Linda Broer9 Reedik Magi10 Richa Saxena11 Jaakko S.Tyrmi12,13 Triin Laisk10,14 Andres Metspalu10 Lili Milani10 Tõnu Esko10 Mari Nelis10 Georgi Hudjashov10 Margrit Urbanek15,16 M. Geoffrey Hayes15,16,17 Gudmar Thorleifsson18 Juan Fernandez-Tajes2 Anubha Mahajan2,19 Kharis A. Burns20,21 Benjamin H. Mullin22 Bronwyn G. A. Stuckey21,22,23 Timothy D. Spector24 Scott G. Wilson22,24 Frank Dudbridge25 Jinrui Cui26 Mark O. Goodarzi26 Ky’Era Actkins27,28,29 Lea K. Davis28,29 Barbara Obermayer-Pietsch30 André G. Uitterlinden9 Verneri Anttila28,31,32 Benjamin M. Neale,31,32 Marjo-Riitta Jarvelin33,34,35,36 Hannele Laivuori12, 37,38,39 Mark Daly11,32,39 Bart Fauser36 Irina Kowalska40 Loes M.E. Moolhuijsen9 Yvonne Louwers5 Jenny A. Visser9 Marianne Andersen41 Ken Ong1 Elisabet Stener-Victorin42 David Ehrmann43 Richard S. Legro44 Andres Salumets12,45,46,47 Mark I. McCarthy2,19,48 Laure Morin-Papunen49 Unnur Thorsteinsdottir18,50 Kari Stefansson18,50 The 23andMe Research Team¶ Unnur Styrkarsdottir18 John R. B. Perry1 Andrea Dunaif15,51 Joop Laven5 Steve Franks52 Cecilia M. Lindgren2,11,53 Corrine K. Welt54,55 International PCOS Consortium Affiliations. 1 MRC Epidemiology Unit, Cambridge Biomedical Campus, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom 2 The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom 3 Department of Biological Sciences, Faculty of Arts and Sciences, Eastern Mediterranean University, Famagusta, Cyprus 4 Center for Bioinformatics & Functional Genomics, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, United States of America 5 Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynaecology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands 6 Department of Internal Medicine, University of Kentucky College of Medicine, Lexington, Kentucky, United States of America 7 University of Kentucky Markey Cancer Center, Lexington, Kentucky, United States of America 8 Departments of Epidemiology and Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America 9 Department of Internal Medicine, Section Endocrinology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands 10 Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia 11 Broad Institute of Harvard and MIT and Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America. 12 Center for Child, Adolescent and Maternal Health Research, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland. 13 Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland. 14 Department of Obstetrics and Gynaecology, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia 15 Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America 16 Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America 17 Department of Anthropology, Northwestern University, Evanston, Illinois, United States of America 18 deCODE genetics/Amgen, Reykjavik, Iceland 19 Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom 20 Department of Endocrinology and Diabetes, Royal Perth Hospital, Perth, WA 6009, Australia. 21 Medical School, University of Western Australia, Nedlands, WA, Australia. 22 Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia 23 Keogh Institute for Medical Research, Nedlands, Western Australia, Australia 24 Department of Twin Research and Genetic Epidemiology, King’s College London, London, United Kingdom 25 Department of Health Sciences, University of Leicester, Leicester, UK. 26 Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, United States of America 27 Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC. 28 Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America 29 Vanderbilt Genomics Institute, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America 30 Division of Endocrinology and Diabetology, Department of Internal Medicine Medical University of Graz, Graz, Austria 31 Stanley Center for Psychiatric Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America 32 Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America 33 Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom 34 Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland 35 Biocenter Oulu, University of Oulu, Oulu, Finland, 31 Unit of Primary Care, Oulu University Hospital, Oulu, Finland 36 Department of Reproductive Medicine and Gynaecology, University Medical Center, Utrecht, The Netherlands 37 Department of Obstetrics and Gynecology, Tampere University Hospital, Tampere, Finland. 38 Medical and Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. 39 Institute for Molecular Medicine Finland, FIMM, hiLIFE, University of Helsinki, Helsinki, Finland. 40 Department of Internal Medicine and Metabolic Diseases, Medical University of Białystok, Białystok, Poland 41 Odense University Hospital, University of Southern Denmark, Odense, Denmark 42 Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden 43 Department of Medicine, Section of Adult and Paediatric Endocrinology, Diabetes, and Metabolism, The University of Chicago, Chicago, Illinois, United States of America 44 Department of Obstetrics and Gynecology and Public Health Sciences, Penn State University College of Medicine, Hershey, Pennsylvania, United States of America 45 Competence Centre on Health Technologies, Tartu, Estonia 46 Institute of Bio- and Translational Medicine, University of Tartu, Tartu, Estonia 47 Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland 48 Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, United Kingdom 49 Department of Obstetrics and Gynecology, University of Oulu and Oulu University Hospital, Medical Research Center, PEDEGO Research Unit, Oulu, Finland 50 Faculty of Medicine, University of Iceland, Reykjavik, Iceland 51 Division of Endocrinology, Diabetes and Bone Disease, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America 52 Institute of Reproductive & Developmental Biology, Department of Surgery & Cancer, Imperial College London, London, United Kingdom 53 Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom 54 Division of Endocrinology, Metabolism and Diabetes, University of Utah, Salt Lake City, Utah, United States of America 55 Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts, United States of America. 23andMe Research Team (23andMe, Inc., Mountain View, California, United States of America): Michelle Agee, Babak Alipanahi, Adam Auton, Robert K. Bell, Katarzyna Bryc, Sarah L. Elson, Pierre Fontanillas, Nicholas A. Furlotte, David A. Hinds, Karen E. Huber, Aaron Kleinman, Nadia Kenref. Litterman, Matthew H. McIntyre, Joanna L. Mountain, Elizabeth S. Noblin, Carrie A.M. Northover, Steven J. Pitts, J. Fah Sathirapongsasuti, Olga V. Sazonova, Janie F. Shelton, Suyash Shringarpure, Chao Tian, Joyce Y. Tung, Vladimir Vacic, Catherine H. Wilson. This study presents independent research supported by the Sir Charles Gairdner Osborne Park Health Care Group, Department of Health (Western Australia), the National Health and Medical Research Council of Australia, Health National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London and the IoPPN Genomics & Biomarker Core Facility, King’s College London. The views expressed are those of the author(s) and not necessarily those of the organisations listed. Cedars Sinai – Mark Goodarzi was supported by the Eris M.Field Chair in Diabetes Research and NIDDK P30-DK063481. Ricardo Azziz was supported by NICHD grants R01-HD29364 and K24-HD01346.; Burns , K , Mullin , B H , Moolhuijsen , L M E , Laisk , T , Tyrmi , J S , Cui , J , Actkins , KE V , Louwers , Y V , Davis , L K , Dudbridge , F , Azziz , R , Goodarzi , M O , Laivuori , H , Mägi , R , Visser , J A , Laven , J S E , Wilson , S G , Day , F R & Stuckey , B G A 2024 , ' Body mass index stratified meta-analysis of genome-wide association studies of polycystic ovary syndrome in women of European ancestry ' , BMC Genomics , vol. 25 , no. 1 , 208 . https://doi.org/10.1186/s12864-024-09990-w; ORCID: /0000-0003-3212-7826/work/160778715; http://hdl.handle.net/10138/574238; 6987603c-7a17-4cd4-a9f0-cf634d2da8f3; 85185962772; 001184639200001
    • Rights:
      cc_by ; info:eu-repo/semantics/openAccess ; openAccess
    • الرقم المعرف:
      edsbas.211578C6