The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study
Thomas W. Winkler, Anne E. Justice(University of North Carolina at Chapel Hill), Mariaelisa Graff(University of North Carolina at Chapel Hill), Llilda Barata(Washington University in St. Louis), Mary F. Feitosa(Washington University in St. Louis), Su H. Chu(University of Michigan), Jacek Czajkowski(Washington University in St. Louis), Tõnu Esko(Broad Institute), Tove Fall(Uppsala University), Tuomas O. Kilpeläinen(University of Copenhagen), Yingchang Lu(Icahn School of Medicine at Mount Sinai), Reedik Mägi(Centre for Human Genetics), Evelin Mihailov, Tune H. Pers(Broad Institute), Sina Rüeger(SIB Swiss Institute of Bioinformatics), Alexander Teumer(Universitätsmedizin Greifswald), Georg Ehret(Johns Hopkins University), Teresa Ferreira(Centre for Human Genetics), Nancy L. Heard‐Costa(Boston University), Juha Karjalainen(University Medical Center Groningen), Vasiliki Lagou(Centre for Human Genetics), Anubha Mahajan(Centre for Human Genetics), Michael D. Neinast(The University of Texas Southwestern Medical Center), Inga Prokopenko(Centre for Human Genetics), Jeannette Simino(Washington University in St. Louis), Tanya M. Teslovich(University of Michigan), Rick Jansen(Amsterdam Public Health), Harm-Jan Westra(Broad Institute), Charles C. White(Boston University), Devin Absher(HudsonAlpha Institute for Biotechnology), Tarunveer S. Ahluwalia(University of Copenhagen), Shafqat Ahmad(Skåne University Hospital), Eva Albrecht(Helmholtz Zentrum München), Alexessander Couto Alves(Imperial College London), Jennifer L. Bragg‐Gresham(University of Michigan), Anton J. M. de Craen(Leiden University Medical Center), Joshua C. Bis(University of Washington), Amélie Bonnefond(Centre National de la Recherche Scientifique), Gabrielle Boucher(Montreal Heart Institute), Gemma Cadby(The University of Western Australia), Yu‐Ching Cheng(University of Maryland, Baltimore), Charleston W. K. Chiang(University of California, Los Angeles), Graciela Delgado(Heidelberg University), Ayşe Demirkan(Erasmus MC), Nicole Dueker(University of Mary), Niina Eklund(University of Helsinki), Guðný Eiríksdóttir(Icelandic Heart Association), Joel Eriksson(Finnish Institute for Health and Welfare), Bjarke Feenstra(Statens Serum Institut), Krista Fischer, Francesca Frau(University of Milan), Tessel E. Galesloot(Radboud University Nijmegen), Frank Geller(Statens Serum Institut), Anuj Goel(Centre for Human Genetics), Mathias Gorski(University Hospital Regensburg), Tanja B. Grammer(Heidelberg University), Stefan Gustafsson(Uppsala University), Saskia Haitjema(Utrecht University), Jouke‐Jan Hottenga, Jennifer E. Huffman(National Heart Lung and Blood Institute), Anne Jackson(University of Michigan), Kevin B. Jacobs(National Institutes of Health), Åsa Johansson(Uppsala University), Marika Kaakinen(Health Protection Agency), Marcus E. Kleber(Heidelberg University), Jari Lahti(University of Helsinki), Irene Mateo Leach(University Medical Center Groningen), Benjamin Lehne(Imperial College London), Youfang Liu(University of North Carolina at Chapel Hill), Ken Sin Lo(Montreal Heart Institute), Mattias Lorentzon(University of Gothenburg), Jian’an Luan(University of Cambridge), Pamela A. F. Madden(Washington University in St. Louis), Massimo Mangino(King's College London), Barbara McKnight(University of Washington), Carolina Medina‐Gómez(Erasmus MC), Keri L. Monda(University of North Carolina at Chapel Hill), May E. Montasser(University of Maryland, Baltimore), Gabriele Müller(University Hospital Carl Gustav Carus), Martina Müller‐Nurasyid(Helmholtz Zentrum München), Ilja M. Nolte(University Medical Center Groningen), Kalliope Panoutsopoulou(Wellcome Sanger Institute), Laura Pascoe(Newcastle University), Lavinia Paternoster(University of Bristol), Nigel W. Rayner(Centre for Human Genetics), Frida Renström(Skåne University Hospital), Federica Rizzi(University of Milan), Lynda M. Rose(Brigham and Women's Hospital), Kathy A. Ryan(University of Maryland, Baltimore), Perttu Salo(Finnish Institute for Health and Welfare), Serena Sanna(Institute of Genetic and Biomedical Research), Hubert Scharnagl(Medical University of Graz), Jianxin Shi(National Cancer Institute), Albert V. Smith(University of Iceland), Lorraine Southam(Centre for Human Genetics), Alena Stančáková(University of Eastern Finland), Valgerður Steinthórsdóttir(deCODE Genetics (Iceland)), Rona J. Strawbridge(Karolinska University Hospital), Yun Ju Sung(Washington University in St. Louis), Ioanna Tachmazidou(Wellcome Sanger Institute), Toshiko Tanaka(National Institute on Aging), Guðmar Þorleifsson(deCODE Genetics (Iceland)), Stella Trompet(Leiden University Medical Center), Natalia Pervjakova(University of Helsinki), Jonathan P. Tyrer(University of Cambridge), Liesbeth Vandenput(University of Gothenburg), Sander W. van der Laan(Utrecht University), Nathalie van der Velde(Erasmus MC), Jessica van Setten(University Medical Center Utrecht), Jana V. van Vliet‐Ostaptchouk(University Medical Center Groningen), Niek Verweij(University Medical Center Groningen), Efthymia Vlachopoulou(University of Helsinki), Lindsay L. Waite(HudsonAlpha Institute for Biotechnology), Sophie R. Wang(Broad Institute), Zhaoming Wang(National Institutes of Health), Sarah H. Wild(University of Edinburgh), Christina Willenborg(Institute for Integrative and Experimental Genomics), James F. Wilson(Centre for Global Health Research), Andrew Wong(MRC Unit for Lifelong Health and Ageing), Jian Yang(The University of Queensland), Loïc Yengo(Centre National de la Recherche Scientifique), Laura M. Yerges-Armstrong(University of Maryland, Baltimore), Lei Yu(Rush University Medical Center), Weihua Zhang(Ealing Hospital), Wei Zhao(University of Cambridge), Ehm A. Andersson(University of Copenhagen), Stephan J. L. Bakker(University Medical Center Groningen), Damiano Baldassarre(University of Milan), Karina Banasik(University of Copenhagen), Matteo Barcella(University of Milan), Cristina Barlassina(University of Milan), Claire Bellis(Texas Biomedical Research Institute), Paola Benaglio(University of California San Diego), John Blangero(Texas Biomedical Research Institute), Matthias Blüher(IFB Adiposity Diseases), Fabrice Bonnet(Université Rennes 2), Lori L. Bonnycastle(National Human Genome Research Institute), Heather A. Boyd(Statens Serum Institut), Marcel Bruinenberg(University Medical Center Groningen), Aron S. Buchman(Rush University Medical Center), Harry Campbell(Centre for Global Health Research), Yii‐Der Ida Chen(Harbor–UCLA Medical Center), Peter S. Chines(National Human Genome Research Institute), Simone Claudi-Boehm(Universität Ulm), John W. Cole(VA Maryland Health Care System), Francis S. Collins(National Human Genome Research Institute), Eco J. C. de Geus(Amsterdam Public Health), C.P.G.M. de Groot(Wageningen University & Research), Maria Dimitriou(Wellcome Sanger Institute), Jubao Duan(NorthShore University HealthSystem), Stefan Enroth(Uppsala University), Elodie Eury(Centre National de la Recherche Scientifique), Aliki‐Eleni Farmaki(Harokopio University of Athens), Nita G. Forouhi(University of Cambridge), Nele Friedrich(Universitätsmedizin Greifswald), Pablo V. Gejman(NorthShore University HealthSystem), Bruna Gigante(Karolinska Institutet), Nicola Glorioso(University of Sassari), Alan S. Go(Kaiser Permanente), Omri Gottesman(Icahn School of Medicine at Mount Sinai), Jürgen Gräßler(Technische Universität Dresden), Harald Grallert(Helmholtz Zentrum München), Niels Grarup(University of Copenhagen), Yumei Gu(KU Leuven), Linda Broer(Erasmus MC), Annelies C. Ham(Erasmus MC), Torben Hansen(University of Copenhagen), Tamara B. Harris(National Institutes of Health), Catharina A. Hartman(University Medical Center Groningen), Maija Hassinen(University of Eastern Finland), Nicholas D. Hastie(Institute of Genetics and Cancer), Andrew T. Hattersley(University of Exeter), Andrew C. Heath(Washington University in St. Louis), Anjali K. Henders(QIMR Berghofer Medical Research Institute), Dena Hernández(National Institutes of Health), Hans L. Hillege(University Medical Center Groningen), Oddgeir L. Holmen(Norwegian University of Science and Technology), Kees Hovingh(Amsterdam UMC Location University of Amsterdam), Jennie Hui(The University of Western Australia), Lise Lotte N. Husemoen(Glostrup Hospital), Nina Hutri‐Kähönen(Tampere University), Pirro G. Hysi(King's College London), Thomas Illig(Helmholtz Zentrum München), Philip L. De Jager(Broad Institute), Shapour Jalilzadeh(Centre for Human Genetics), Torben Jørgensen(University of Copenhagen), J. Wouter Jukema(Leiden University Medical Center), Markus Juonala(University of Turku), Stavroula Kanoni(Queen Mary University of London), Maria Karaleftheri(Athens Medical Center), Kay‐Tee Khaw(Addenbrooke's Hospital), Leena Kinnunen(Finnish Institute for Health and Welfare), Steven J. Kittner(VA Maryland Health Care System), Wolfgang Köenig(Universität Ulm), Ivana Kolčić(University of Split), Péter Kovács(IFB Adiposity Diseases), Nikolaj T. Krarup(University of Copenhagen), Wolfgang Kratzer(Universität Ulm), Janine Krüger(Universitätsmedizin Greifswald), Diana Kuh(MRC Unit for Lifelong Health and Ageing), Meena Kumari(University College London), Theodosios Kyriakou(Centre for Human Genetics), Claudia Langenberg(University of Cambridge), Lars Lannfelt(Uppsala University), Chiara Lanzani(Vita-Salute San Raffaele University), Vaneet Lotay(University of Calgary), Lenore J. Launer(National Institutes of Health), Karin Leander(Karolinska Institutet), Jaana Lindström(Finnish Institute for Health and Welfare), Allan Linneberg(University of Copenhagen), Yanping Liu(University of North Carolina at Chapel Hill), Stéphane Lobbens(Centre National de la Recherche Scientifique), Robert Luben, Valeriya Lyssenko(Steno Diabetes Centers), Satu Männistö(Finnish Institute for Health and Welfare), Patrik K. E. Magnusson(Karolinska Institutet), Wendy L. McArdle(University of Bristol), Cristina Menni(King's College London), Sigrun Merger(Universität Ulm), Lili Milani, Grant W. Montgomery(QIMR Berghofer Medical Research Institute), Andrew P. Morris(Centre for Human Genetics), Narisu Narisu(National Human Genome Research Institute), Mari Nelis, Ken K. Ong(University of Cambridge), Aarno Palotie(University of Helsinki), Louis Përusse(Université Laval), Irene Pichler(Eurac Research), Maria Grazia Pilia(Institute of Genetic and Biomedical Research), Anneli Pouta(Oulu University Hospital), Myriam Rheinberger(University Hospital Regensburg), Rasmus Ribel‐Madsen(University of Copenhagen), Marcus Richards(MRC Unit for Lifelong Health and Ageing), Kenneth Rice(University of Washington), Treva Rice(Washington University in St. Louis), Carlo Rivolta(University of Lausanne), Veikko Salomaa(Finnish Institute for Health and Welfare), Alan R. Sanders(NorthShore University HealthSystem), Mark A. Sarzynski(Pennington Biomedical Research Center), Salome Scholtens(University Medical Center Groningen), Robert A. Scott(University of Cambridge), William R. Scott(Ealing Hospital), Sylvain Sebért(University of Oulu), Sebanti Sengupta(University of Michigan), Bengt Sennblad(Karolinska University Hospital), Thomas Seufferlein(Universität Ulm), Angela Silveira(Karolinska University Hospital), P. Eline Slagboom(Leiden University Medical Center), Jan Smit(Amsterdam Public Health), Thomas Sparsø(University of Copenhagen), Kathleen Stirrups(Queen Mary University of London), Ronald P. Stolk(University Medical Center Groningen), Heather M. Stringham(University of Michigan), Morris A. Swertz(University Medical Center Groningen), Amy J. Swift(National Human Genome Research Institute), Ann‐Christine Syvänen(Uppsala University), Sian-Tsung Tan(Ealing Hospital), Barbara Thorand(Helmholtz Zentrum München), Anke Tönjes(Leipzig University), Angelo Tremblay(Université Laval), Emmanouil Tsafantakis, Peter J. van der Most(University Medical Center Groningen), Uwe Völker(Universitätsmedizin Greifswald), Marie‐Claude Vohl(Université Laval), Judith M. Vonk(University Medical Center Groningen), Mélanie Waldenberger(Helmholtz Zentrum München), Ryan W. Walker(Icahn School of Medicine at Mount Sinai), Roman Wennauer(Universität Ulm), Elisabeth Widén(University of Helsinki), Gonneke Willemsen, Tom Wilsgaard(University of Oslo), Alan F. Wright(Institute of Genetics and Cancer), M. Carola Zillikens(Erasmus MC), Suzanne C. van Dijk(Erasmus MC), Natasja M. van Schoor(Amsterdam Public Health), Folkert W. Asselbergs(University Medical Center Utrecht), Paul I. W. de Bakker(Utrecht University), J. Beckmann(SIB Swiss Institute of Bioinformatics), John Beilby(The University of Western Australia), David A. Bennett(Rush University Medical Center), Richard N. Bergman(Cedars-Sinai Medical Center), Sven Bergmann(SIB Swiss Institute of Bioinformatics), Carsten A. Böger(University Hospital Regensburg), Bernhard O. Boehm(Nanyang Technological University), Eric Boerwinkle(The University of Texas Health Science Center at Houston), Dorret I. Boomsma, Stefan R. Bornstein(University Hospital Carl Gustav Carus), Erwin P. Böttinger(Icahn School of Medicine at Mount Sinai), Claude Bouchard(Pennington Biomedical Research Center), John C. Chambers(Imperial College Healthcare NHS Trust), Stephen J. Chanock(National Institutes of Health), Daniel I. Chasman(Brigham and Women's Hospital), Francesco Cucca(University of Sassari), Daniele Cusi(University of Milan), George Dedoussis(Harokopio University of Athens), Jeanette Erdmann(Institute for Integrative and Experimental Genomics), Johan G. Eriksson(University of Helsinki), Denis A. Evans(Rush University Medical Center), Ulf dé Fairé(Karolinska Institutet), Martin Farrall(Centre for Human Genetics), Luigi Ferrucci(National Institute on Aging), Ian Ford(University of Glasgow), Lude Franke(University Medical Center Groningen), Paul W. Franks(Harvard University), Philippe Froguel(Centre National de la Recherche Scientifique), Ron T. Gansevoort(University Medical Center Groningen), Christian Gieger(Helmholtz Zentrum München), Henrik Grönberg(Karolinska Institutet), Vilmundur Guðnason(University of Iceland), Ulf Gyllensten(Uppsala University), Per Hall(Karolinska Institutet), Anders Hamsten(Karolinska University Hospital), Pim van der Harst(University Medical Center Groningen), Caroline Hayward(Institute of Genetics and Cancer), Markku Heliövaara(Finnish Institute for Health and Welfare), Christian Hengstenberg(German Centre for Cardiovascular Research), Andrew A. Hicks(Eurac Research), Aroon D. Hingorani(University College London), Albert Hofman(Erasmus MC), Frank B. Hu(Brigham and Women's Hospital), Heikki V. Huikuri(Oulu University Hospital), Kristian Hveem(Norwegian University of Science and Technology), Alan L. James(Sir Charles Gairdner Hospital), Joanne M. Jordan(University of North Carolina at Chapel Hill), Antti Jula(Finnish Institute for Health and Welfare), Mika Kähönen(Tampere University), Eero Kajantie(University of Helsinki), Sekar Kathiresan(Broad Institute), Lambertus A. Kiemeney(Radboud University Nijmegen), Mika Kivimäki(University College London), Paul Knekt(Finnish Institute for Health and Welfare), Heikki A. Koistinen(University of Helsinki), Jaspal S. Kooner(Imperial College Healthcare NHS Trust), Seppo Koskinen(Finnish Institute for Health and Welfare), Johanna Kuusisto(University of Eastern Finland), Winfried Maerz(Medical University of Graz), Nicholas G. Martin(QIMR Berghofer Medical Research Institute), Markku Laakso(University of Eastern Finland), Timo A. Lakka(University of Eastern Finland), Terho Lehtimäki(Tampere University), Guillaume Lettre(Montreal Heart Institute), Douglas F. Levinson(Stanford University), Lars Lind(Uppsala University), Marja‐Liisa Lokki(University of Helsinki), Pekka Mäntyselkä(University of Eastern Finland), Mads Melbye(Statens Serum Institut), Andres Metspalu, Braxton D. Mitchell(University of Maryland, Baltimore), Frans L. Moll(University Medical Center Utrecht), Jeffrey C. Murray(University of Iowa), Arthur W. Musk(Sir Charles Gairdner Hospital), Markku S. Nieminen(Helsinki University Hospital), Inger Njølstad(University of Oslo), Claes Ohlsson(University of Gothenburg), Albertine J. Oldehinkel(University Medical Center Groningen), Ben A. Oostra(Erasmus MC), Lyle J. Palmer(The University of Adelaide), James S. Pankow(University of Minnesota), Gerard Pasterkamp(Utrecht University), Nancy L. Pedersen(Karolinska Institutet), Oluf Pedersen(University of Copenhagen), Brenda W.J.H. Penninx(Amsterdam Public Health), Markus Perola(University of Helsinki), Annette Peters(Helmholtz Zentrum München), Ozren Polašek(Centre for Global Health Research), Peter P. Pramstaller(Eurac Research), Bruce M. Psaty(Group Health Cooperative), Lu Qi(Brigham and Women's Hospital), Thomas Quertermous(Stanford University), Olli T. Raitakari(University of Turku), Tuomo Rankinen(Pennington Biomedical Research Center), Rainer Rauramaa(University of Eastern Finland), Paul M. Ridker(Brigham and Women's Hospital), John D. Rioux(Montreal Heart Institute), Fernando Rivadeneira(Erasmus MC), Jerome I. Rotter(Harbor–UCLA Medical Center), Igor Rudan(Centre for Global Health Research), Hester M. den Ruijter(Utrecht University), Juha Saltevo(Central Finland Health Care District), Naveed Sattar(University of Glasgow), Heribert Schunkert(German Centre for Cardiovascular Research), Peter Schwarz(University Hospital Carl Gustav Carus), Alan R. Shuldiner(University of Maryland, Baltimore), Juha Sinisalo(Helsinki University Hospital), Harold Snieder(University Medical Center Groningen), Thorkild I. A. Sørensen(University of Copenhagen), Tim D. Spector(King's College London), Jan A. Staessen(Maastricht University), Bandinelli Stefania(Azienda Sanitaria di Firenze), Unnur Þorsteinsdóttir(deCODE Genetics (Iceland)), Michael Stümvoll(IFB Adiposity Diseases), Jean‐Claude Tardif(Montreal Heart Institute), Elena Tremoli(University of Milan), Jaakko Tuomilehto(Universität für Weiterbildung Krems), André G. Uitterlinden(Erasmus MC), Matti Uusitupa(University of Eastern Finland), André L. M. Verbeek(Radboud University Nijmegen), Sita H. Vermeulen(Radboud University Nijmegen), Jorma Viikari(University of Turku), Véronique Vitart(Institute of Genetics and Cancer), Henry Völzke(Universitätsmedizin Greifswald), Péter Vollenweider(University of Lausanne), Gérard Waeber(University of Lausanne), Mark Walker(Broad Institute), Henri Wallaschofski(Universitätsmedizin Greifswald), Nicholas J. Wareham(University of Cambridge), Hugh Watkins(Centre for Human Genetics), Eleftheria Zeggini(Wellcome Sanger Institute), Aravinda Chakravarti(Johns Hopkins University), Deborah J. Clegg(The University of Texas Southwestern Medical Center), L. Adrienne Cupples(Boston University), Penny Gordon‐Larsen(University of North Carolina at Chapel Hill), Cashell E. Jaquish(National Heart Lung and Blood Institute), D. C. Rao(Washington University in St. Louis), Gonçalo R. Abecasis(University of Michigan), Themistocles L. Assimes(Stanford University), Inês Barroso(University of Cambridge), Sonja I. Berndt(National Institutes of Health), Michael Boehnke(University of Michigan), Panos Deloukas(Queen Mary University of London), Caroline S. Fox(Harvard University), Leif Groop(Lund University), David J. Hunter(Broad Institute), Erik Ingelsson(Uppsala University), Robert C. Kaplan(Albert Einstein College of Medicine), Mark I. McCarthy(Centre for Human Genetics), Karen L. Mohlke(University of North Carolina at Chapel Hill), Jeffrey R. O’Connell(University of Maryland, Baltimore), David Schlessinger(National Institutes of Health), David P. Strachan(St George's, University of London), Kāri Stefánsson(deCODE Genetics (Iceland)), Cornelia M. van Duijn(Erasmus MC), Joel N. Hirschhorn(Broad Institute), Cecilia M. Lindgren(Broad Institute), Iris M. Heid(Helmholtz Zentrum München), Kari E. North(University of North Carolina at Chapel Hill), Ingrid B. Borecki(Washington University in St. Louis), Zoltán Kutalik(SIB Swiss Institute of Bioinformatics), Ruth J. F. Loos(University of Cambridge)
Cited by 689Open Access
Abstract
Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.
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