Sex-stratified Genome-wide Association Studies Including 270,000 Individuals Show Sexual Dimorphism in Genetic Loci for Anthropometric Traits
Joshua C. Randall(Centre for Human Genetics), Thomas W. Winkler(University of Regensburg), Zoltán Kutalik(SIB Swiss Institute of Bioinformatics), Sonja I. Berndt(National Institutes of Health), Anne Jackson(University of Michigan), Keri L. Monda(University of North Carolina at Chapel Hill), Tuomas O. Kilpeläinen(Addenbrooke's Hospital), Tõnu Esko(University of Tartu), Reedik Mägi(Centre for Human Genetics), Shengxu Li(Tulane University), Tsegaselassie Workalemahu(Harvard University), Mary F. Feitosa(Washington University in St. Louis), Damien C. Croteau‐Chonka(University of North Carolina at Chapel Hill), Felix R. Day(Addenbrooke's Hospital), Tove Fall(Karolinska Institutet), Teresa Ferreira(Centre for Human Genetics), Stefan Gustafsson(Karolinska Institutet), Adam E. Locke(University of Michigan), Iain Mathieson(Centre for Human Genetics), André Scherag(Institut für Medizinische Informatik, Biometrie und Epidemiologie), Sailaja Vedantam(Broad Institute), Andrew R. Wood(University of Exeter), Liming Liang(Harvard University), Valgerður Steinthórsdóttir(deCODE Genetics (Iceland)), Guðmar Þorleifsson(deCODE Genetics (Iceland)), Emmanouil T. Dermitzakis(University of Geneva), Antigone S. Dimas(University of Geneva), Fredrik Karpe(University of Oxford), Josine L. Min(Centre for Human Genetics), George Nicholson(University of Oxford), Deborah J. Clegg(The University of Texas Southwestern Medical Center), Thomas N. Person(The University of Texas Southwestern Medical Center), Jon P. Krohn(Centre for Human Genetics), Sabrina Bauer(University Hospital Regensburg), Christa Buechler(University Hospital Regensburg), Kristina Eisinger(University Hospital Regensburg), Amélie Bonnefond(Centre National de la Recherche Scientifique), Philippe Froguel(University of Maryland, Baltimore), MAGIC Investigators(Vrije Universiteit Amsterdam), Jouke‐Jan Hottenga(Centre for Human Genetics), Inga Prokopenko(Centre for Human Genetics), Lindsay L. Waite(National Institutes of Health), Tamara B. Harris(University of Iceland), Albert V. Smith(University of Maryland, Baltimore), Alan R. Shuldiner(University of Bristol), Wendy L. McArdle(Queen Mary University of London), Mark J. Caulfield(Queen Mary University of London), Patricia B. Munroe(Karolinska Institutet), Henrik Grönberg(Cedars-Sinai Medical Center), Yii-Der Ida Chen(University of Washington), Li Guo(University Hospital of Lausanne), J. Beckmann(SIB Swiss Institute of Bioinformatics), Toby Johnson(SIB Swiss Institute of Bioinformatics), Unnur Þorsteinsdóttir(deCODE Genetics (Iceland)), Maris Teder‐Laving(University of Cambridge), Kay‐Tee Khaw(Addenbrooke's Hospital), Nicholas J. Wareham(Addenbrooke's Hospital), Wei Zhao(Erasmus MC), Najaf Amin(Erasmus MC), Ben A. Oostra(Washington University in St. Louis), Aldi T. Kraja(Washington University in St. Louis), Michael A. Province(Boston University), L. Adrienne Cupples(Boston University), Nancy L. Heard‐Costa(University of Helsinki), Jaakko Kaprio(University of Helsinki), Samuli Ripatti(University of Helsinki), Ida Surakka(University of Helsinki), Francis S. Collins(National Human Genome Research Institute), Jouko Saramies(Universität für Weiterbildung Krems), Jaakko Tuomilehto(Finnish Institute for Health and Welfare), Antti Jula(Finnish Institute for Health and Welfare), Veikko Salomaa(Finnish Institute for Health and Welfare), Jeanette Erdmann(Becker Technologies (Germany)), Christian Hengstenberg(Institut für Angewandte Statistik), Christina Loley(Becker Technologies (Germany)), Heribert Schunkert(Innsbruck Medical University), Claudia Lamina(Innsbruck Medical University), H.-Erich Wichmann(Zimmer Biomet (Netherlands)), Eva Albrecht(Helmholtz Zentrum München), Christian Gieger(Eurac Research), Andrew A. Hicks(Uppsala University), Åsa Johansson(Eurac Research), Peter P. Pramstaller(Broad Institute), Sekar Kathiresan(University of Michigan), Elizabeth K. Speliotes(University Medical Center Groningen), Brenda W.J.H. Penninx(University of Oulu), Anna-Liisa Hartikainen(Finnish Institute for Health and Welfare), Marjo‐Riitta Järvelin(Uppsala University), Ulf Gyllensten(Vrije Universiteit Amsterdam), Dorret I. Boomsma(University of Edinburgh), Harry Campbell(University of Edinburgh), James F. Wilson(National Institutes of Health), Stephen J. Chanock(Centre for Human Genetics), Martin Farrall(Centre for Human Genetics), Anuj Goel(Erasmus MC), Carolina Medina‐Gómez(Erasmus MC), Fernando Rivadeneira(Erasmus MC), Karol Estrada(Erasmus MC), André G. Uitterlinden(Erasmus MC), Albert Hofman(Erasmus MC), M. Carola Zillikens(Amsterdam UMC Location Vrije Universiteit Amsterdam), Martin den Heijer(Radboud University Nijmegen), Lambertus A. Kiemeney(Institute of Genetic and Biomedical Research), Andrea Maschio(Karolinska Institutet), Per Hall(University of Cambridge), Jonathan P. Tyrer(Universität Greifswald), Alexander Teumer(Universitätsmedizin Greifswald), Henry Völzke, Péter Kovács(IFB Adiposity Diseases), Anke Tönjes(King's College London), Massimo Mangino(King's College London), Tim D. Spector(Western General Hospital), Caroline Hayward(University of Tartu), Igor Rudan(University of Leeds), Alistair S. Hall(University of Leicester), Nilesh J. Samani(University of Cambridge), Antony Attwood(NHS Blood and Transplant), Jennifer G. Sambrook(The University of Western Australia), Joseph Hung(Ontario Institute for Cancer Research), Lyle J. Palmer(University of Helsinki), Marja‐Liisa Lokki(Helsinki University Hospital), Juha Sinisalo(Montreal Heart Institute), Gabrielle Boucher(Boston Children's Hospital), Heikki V. Huikuri(Broad Institute), Mattias Lorentzon(University of Gothenburg), Claes Ohlsson(Finnish Institute for Health and Welfare), Niina Eklund(University of Helsinki), Johan G. Eriksson(University of Milan), Cristina Barlassina(University of Lausanne), Carlo Rivolta(Tulane University), Ilja M. Nolte(University of Geneva), Harold Snieder(University Medical Center Groningen), Melanie M. van der Klauw(University Medical Center Groningen), Jana V. van Vliet‐Ostaptchouk(Centre for Human Genetics), Pablo V. Gejman(National Institutes of Health), Jianxin Shi(Tulane University), Kevin B. Jacobs(National Institutes of Health), Zhaoming Wang(University Medical Center Groningen), Stephan J. L. Bakker(University Medical Center Groningen), Irene Mateo Leach(University Medical Center Groningen), Gerjan Navis(University Medical Center Groningen), Pim van der Harst(QIMR Berghofer Medical Research Institute), Nicholas G. Martin(Harvard University), Sarah E. Medland(Harvard University), Grant W. Montgomery(Harvard University), Jian Yang(Brigham and Women's Hospital), Daniel I. Chasman(Brigham and Women's Hospital), Paul M. Ridker(Brigham and Women's Hospital), Lynda M. Rose(Harvard University), Terho Lehtimäki(University of Turku), Olli T. Raitakari(Harvard University), Devin Absher(Kaiser Permanente), Carlos Iribarren(Harvard University), Hanneke Basart(Washington University in St. Louis), Kees Hovingh(Washington University in St. Louis), Elina Hyppönen, Chris Power(The Kids Research Institute Australia), Denise Anderson(The University of Western Australia), John Beilby(The University of Western Australia), Jennie Hui(University of Cambridge), Jennifer Jolley(University of Lübeck), Hendrik B. Sager(University of North Carolina at Chapel Hill), Stefan R. Bornstein(University of North Carolina at Chapel Hill), Peter Schwarz(University of North Carolina at Chapel Hill), Kati Kristiansson(University of Helsinki), Markus Perola(Finnish Institute for Health and Welfare), Jaana Lindström(National Human Genome Research Institute), Amy J. Swift(University of Eastern Finland), Matti Uusitupa(University of North Carolina at Chapel Hill), Mustafa Atalay(Boston University), Timo A. Lakka(University of Eastern Finland), Rainer Rauramaa(University of Edinburgh), Jennifer L. Bolton(University of North Carolina at Chapel Hill), Gerry Fowkes(University of North Carolina at Chapel Hill), Ross M. Fraser(University of North Carolina at Chapel Hill), Jackie F. Price(University of Tartu), Krista Fischer(University of Tartu), Kaarel KrjutÅ¡kov(University of Tartu), Andres Metspalu(University of Tartu), Evelin Mihailov(Addenbrooke's Hospital), Claudia Langenberg(Addenbrooke's Hospital), Jian’an Luan(MRC Unit for Lifelong Health and Ageing), Ken K. Ong(National Human Genome Research Institute), Peter S. Chines(Oulu University Hospital), Sirkka Keinänen‐Kiukaanniemi(Finnish Diabetes Association), Timo Saaristo(Wellcome Sanger Institute), Sarah Edkins(Harvard University), Paul W. Franks(Umeå University), Göran Hallmans(Lund University), Dmitry Shungin(University of Dundee), Andrew David Morris(University of Dundee), Colin N. A. Palmer(Karolinska Institutet), Raimund Erbel(Karolinska Institutet), Susanne Moebus(University of Bonn), Markus M. Nöthen(Institut für Medizinische Informatik, Biometrie und Epidemiologie), Sonali Pechlivanis(Norwegian University of Science and Technology), Kristian Hveem(National Human Genome Research Institute), Narisu Narisu(Karolinska University Hospital), Anders Hamsten(Center for Environmental Health), Steve E. Humphries(Karolinska University Hospital), Rona J. Strawbridge(University of Milan), Elena Tremoli(Helmholtz Zentrum München), Harald Grallert(Helmholtz Zentrum München), Barbara Thorand(Helmholtz Zentrum München), Thomas Illig(Universität Ulm), Wolfgang Köenig(Helmholtz Zentrum München), Martina Müller‐Nurasyid(Helmholtz Zentrum München), Annette Peters(Boston Children's Hospital), Bernhard O. Boehm(Boston Children's Hospital), Marcus E. Kleber(Boston Children's Hospital), Winfried März(Kardiologie Frankfurt-Sachsenhausen), Bernhard R. Winkelmann(Boston Children's Hospital), Johanna Kuusisto(Boston Children's Hospital), Markku Laakso(Boston Children's Hospital), Dominique Arveiler(Boston Children's Hospital), Giancarlo Cesana(Boston Children's Hospital), Kari Kuulasmaa(Boston Children's Hospital), Jarmo Virtamo(Queen's University Belfast), J. W. G. Yarnell(Boston Children's Hospital), Diana Kuh(University of North Carolina at Chapel Hill), Andrew Wong(University of North Carolina at Chapel Hill), Lars Lind(Broad Institute), Ulf dé Fairé(Broad Institute), Bruna Gigante(Broad Institute), Patrik K. E. Magnusson(Karolinska Institutet), Nancy L. Pedersen(Karolinska Institutet), George Dedoussis(Broad Institute), Maria Dimitriou(Broad Institute), Genovefa Kolovou(Broad Institute), Stavroula Kanoni(Wellcome Sanger Institute), Kathleen Stirrups(Wellcome Sanger Institute), Lori L. Bonnycastle(National Human Genome Research Institute), Inger Njølstad(Broad Institute), Tom Wilsgaard(Broad Institute), Andrea Ganna(Karolinska Institutet), Emil Rehnberg(Karolinska Institutet), Aroon D. Hingorani(University of North Carolina at Chapel Hill), Mika Kivimäki(University of North Carolina at Chapel Hill), Meena Kumari(University of North Carolina at Chapel Hill), Themistocles L. Assimes(Broad Institute), Inês Barroso(Broad Institute), Michael Boehnke(Washington University in St. Louis), Ingrid B. Borecki(Washington University in St. Louis), Panos Deloukas(Wellcome Sanger Institute), Caroline S. Fox(Broad Institute), Timothy M. Frayling(Lund University), Leif C. Groop(Broad Institute), Talin Haritunians(Broad Institute), David J. Hunter(Karolinska Institutet), Erik Ingelsson(Albert Einstein College of Medicine), Robert C. Kaplan(University of North Carolina at Chapel Hill), Karen L. Mohlke(University of North Carolina at Chapel Hill), Jeffrey R. O’Connell(National Institute on Aging), David Schlessinger(Harvard University), David P. Strachan(deCODE Genetics (Iceland)), Kāri Stefánsson(deCODE Genetics (Iceland)), Cornelia M. van Duijn(Harvard University), Gonçalo R. Abecasis(Centre for Human Genetics), Mark I. McCarthy(Broad Institute), Joel N. Hirschhorn(Brigham and Women's Hospital), Lu Qi(Harvard University), Ruth J. F. Loos(Centre for Human Genetics), Cecilia M. Lindgren(University of North Carolina at Chapel Hill), Kari E. North(University of North Carolina at Chapel Hill), Iris M. Heid(University of Regensburg)
Cited by 458Open Access
Abstract
Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.