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      Genome-wide physical activity interactions in adiposity ― A meta-analysis of 200,452 adults

      research-article
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          Abstract

          Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.

          Author summary

          Decline in daily physical activity is thought to be a key contributor to the global obesity epidemic. However, the impact of sedentariness on adiposity may be in part determined by a person’s genetic constitution. The specific genetic variants that are sensitive to physical activity and regulate adiposity remain largely unknown. Here, we aimed to identify genetic variants whose effects on adiposity are modified by physical activity by examining ~2.5 million genetic variants in up to 200,452 individuals. We also tested whether adjusting for physical activity as a covariate could lead to the identification of novel adiposity variants. We find robust evidence of interaction with physical activity for the strongest known obesity risk-locus in the FTO gene, of which the body mass index-increasing effect is attenuated by ~30% in physically active individuals compared to inactive individuals. Our analyses indicate that other similar gene-physical activity interactions may exist, but better measurement of physical activity, larger sample sizes, and/or improved analytical methods will be required to identify them. Adjusting for physical activity, we identify 11 novel adiposity variants, suggesting that accounting for physical activity or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.

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          Integrative analysis of 111 reference human epigenomes

          The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but a similar reference has lacked for epigenomic studies. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection to-date of human epigenomes for primary cells and tissues. Here, we describe the integrative analysis of 111 reference human epigenomes generated as part of the program, profiled for histone modification patterns, DNA accessibility, DNA methylation, and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically-relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation, and human disease.
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            LD Score regression distinguishes confounding from polygenicity in genome-wide association studies.

            Both polygenicity (many small genetic effects) and confounding biases, such as cryptic relatedness and population stratification, can yield an inflated distribution of test statistics in genome-wide association studies (GWAS). However, current methods cannot distinguish between inflation from a true polygenic signal and bias. We have developed an approach, LD Score regression, that quantifies the contribution of each by examining the relationship between test statistics and linkage disequilibrium (LD). The LD Score regression intercept can be used to estimate a more powerful and accurate correction factor than genomic control. We find strong evidence that polygenicity accounts for the majority of the inflation in test statistics in many GWAS of large sample size.
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              METAL: fast and efficient meta-analysis of genomewide association scans

              Summary: METAL provides a computationally efficient tool for meta-analysis of genome-wide association scans, which is a commonly used approach for improving power complex traits gene mapping studies. METAL provides a rich scripting interface and implements efficient memory management to allow analyses of very large data sets and to support a variety of input file formats. Availability and implementation: METAL, including source code, documentation, examples, and executables, is available at http://www.sph.umich.edu/csg/abecasis/metal/ Contact: goncalo@umich.edu
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, CA USA )
                1553-7390
                1553-7404
                27 April 2017
                April 2017
                : 13
                : 4
                : e1006528
                Affiliations
                [1 ]Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
                [2 ]MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
                [3 ]Carolina Population Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
                [4 ]Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, United States of America
                [5 ]Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany
                [6 ]National Heart, Lung, and Blood Institute, Framingham Heart Study, Framingham, Massachusetts, United States of America
                [7 ]Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America
                [8 ]Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
                [9 ]Division of Population Health Sciences and Education, St. George's, University of London, London, United Kingdom
                [10 ]Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America
                [11 ]Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America
                [12 ]Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, United States of America
                [13 ]Department of Immunology, Genetics and Pathology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
                [14 ]Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
                [15 ]Steno Diabetes Center, Gentofte, Denmark
                [16 ]Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, United States of America
                [17 ]Howard University, Department of Internal Medicine, Washington DC, United States of America
                [18 ]Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden
                [19 ]Department of Biobank Research, Umeå University, Umeå, Sweden
                [20 ]Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom
                [21 ]Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, The Framingham Heart Study, Framingham, Massachusetts, United States of America
                [22 ]Cell and Developmental Biology Graduate Program, Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, New York, United States of America
                [23 ]Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
                [24 ]Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America
                [25 ]Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America
                [26 ]Institute of Social and Preventive Medicine, Lausanne University Hospital, Lausanne, Switzerland
                [27 ]Swiss Institute of Bioinformatics, Lausanne, Switzerland
                [28 ]MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom
                [29 ]Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
                [30 ]Department of Cardiology, Ealing Hospital HNS Trust, Middlesex, United Kingdom
                [31 ]Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan, United States of America
                [32 ]Estonian Genome Center, University of Tartu, Tartu, Estonia
                [33 ]Department of Internal Medicine, Internal Medicine, Lausanne University Hospital, Lausanne, Switzerland
                [34 ]Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
                [35 ]University of Lille, CNRS, Institut Pasteur de Lille, UMR 8199 - EGID, Lille, France
                [36 ]Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
                [37 ]DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald, Germany
                [38 ]Icelandic Heart Association, Kopavogur, Iceland
                [39 ]Faculty of Medicine, University of Iceland, Reykjavik, Iceland
                [40 ]ISER, University of Essex, Colchester, Essex, United Kingdom
                [41 ]Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
                [42 ]Institute of Nutrition, Friedrich Schiller University Jena, Jena, Germany
                [43 ]Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America
                [44 ]Karolinska Institutet, Respiratory Unit, Department of Medicine Solna, Stockholm, Sweden
                [45 ]Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Australia
                [46 ]Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, United States of America
                [47 ]Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland
                [48 ]Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere, Finland
                [49 ]Department of Biological Psychology, Vrije Universiteit, Amsterdam, The Netherlands
                [50 ]EMGO+ Institute, Vrije Universiteit & VU University Medical Center, Amsterdam, The Netherlands
                [51 ]Department of Public and Occupational Health, VU University Medical Center, Amsterdam, The Netherlands
                [52 ]Department of Psychiatry, EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, VU University Medical Center/GGZ InGeest, Amsterdam, The Netherlands
                [53 ]Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, United States of America
                [54 ]National Institute for Health and Welfare, Department of Health, Helsinki, Finland
                [55 ]Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
                [56 ]Genetic Epidemiology Unit, Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands
                [57 ]Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
                [58 ]Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, United States of America
                [59 ]Division of Epidemiology, Human Genetics, and Environmental Sciences, University of Texas Health Science Center at Houston, Houston, Texas, United States of America
                [60 ]Kuopio Research Institute of Exercise Medicine, Kuopio, Finland
                [61 ]Centre for Genetic Origins of Health and Disease, University of Western Australia, Crawley, Western Australia, Australia
                [62 ]Translational Gerontology Branch, National Institute on Aging, Baltimore, Maryland, United States of America
                [63 ]Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
                [64 ]Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research of Singapore, Singapore
                [65 ]Genomics Research Centre, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia
                [66 ]Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, United Kingdom
                [67 ]Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
                [68 ]Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland, United States of America
                [69 ]Veterans Affairs Maryland Health Care System, University of Maryland, Baltimore, Maryland, United States of America
                [70 ]Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
                [71 ]Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, United States of America
                [72 ]Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark
                [73 ]Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
                [74 ]Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
                [75 ]INSERM U-1018, CESP, Renal and Cardiovascular Epidemiology, UVSQ-UPS, Villejuif, France
                [76 ]Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland
                [77 ]Unit of Primary Care, Oulu University Hospital, Oulu, Finland
                [78 ]Busselton Population Medical Research Institute, Nedlands, Western Australia, Australia
                [79 ]PathWest Laboratory Medicine of WA, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia
                [80 ]School of Pathology and Laboratory Medicine, The University of Western Australia, Crawley, Western Australia, Australia
                [81 ]Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America
                [82 ]Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
                [83 ]Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America
                [84 ]Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America
                [85 ]Texas Biomedical Research Institute, San Antonio, Texas, United States of America
                [86 ]Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, United States of America
                [87 ]USC-Office of Population Studies Foundation, Inc., University of San Carlos, Cebu City, Philippines
                [88 ]Department of Nutrition and Dietetics, University of San Carlos, Cebu City, Philippines
                [89 ]Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale Delle Ricerche (CNR), Cittadella Universitaria di Monserrato, Monserrato, Italy
                [90 ]Department of Genetics, Rutgers University, Piscataway, New Jersey, United States of America
                [91 ]Department of Statistics and Biostatistics, Rutgers University, Piscataway, New Jersey, United States of America
                [92 ]Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, Edinburgh, Scotland
                [93 ]MRC Integrative Epidemiology Unit & School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom
                [94 ]University of Maryland School of Medicine, Department of Epidemiology & Public Health, Baltimore, Maryland, United States of America
                [95 ]Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany
                [96 ]Department of Medicine, Oulu University Hospital, Oulu, Finland
                [97 ]Institute of Clinical Medicine, Faculty of Medicine, University of Oulu, Oulu, Finland
                [98 ]Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, United States of America
                [99 ]Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America
                [100 ]Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, United States of America
                [101 ]Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, Michigan, United States of America
                [102 ]Research Unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
                [103 ]Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
                [104 ]Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany
                [105 ]German Center for Diabetes Research (DZD), München-Neuherberg, Germany
                [106 ]Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland, United States of America
                [107 ]Division of Genomic Medicine, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America
                [108 ]Musculoskeletal Research Programme, Division of Applied Medicine, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom
                [109 ]Generation Scotland, Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, United Kingdom
                [110 ]St. Olav Hospital, Trondheim University Hospital, Trondheim, Norway
                [111 ]Institute for Nutritional Medicine, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany
                [112 ]NCA Institute, VU University & VU Medical Center, Amsterdam, The Netherlands
                [113 ]Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom
                [114 ]School of Population Health, The University of Western Australia, Crawley, Western Australia, Australia
                [115 ]Department of Pediatrics, Tampere University Hospital, Tampere, Finland
                [116 ]Department of Pediatrics, University of Tampere School of Medicine, Tampere, Finland
                [117 ]Department of Pulmonary Physiology and Sleep Medicine, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia
                [118 ]School of Medicine and Pharmacology, The University of Western Australia, Crawley, Western Australia, Australia
                [119 ]Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
                [120 ]Department of Medicine, University of Turku, Turku, Finland
                [121 ]Division of Medicine, Turku University Hospital, Turku, Finland
                [122 ]National Institute for Health and Welfare, Department of Health, Helsinki, Finland
                [123 ]Department of Medicine and Abdominal Center: Endocrinology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
                [124 ]Minerva Foundation Institute for Medical Research, Helsinki, Finland
                [125 ]Department of Public Health, Faculty of Medicine, University of Split, Split, Croatia
                [126 ]Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
                [127 ]HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Norway
                [128 ]Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland
                [129 ]Department of Clinical Physiology, University of Tampere School of Medicine, Tampere, Finland
                [130 ]Institute of Biomedicine, Physiology, University of Eastern Finland, Kuopio Campus, Finland
                [131 ]Neuroepidemiology Section, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America
                [132 ]Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America
                [133 ]The Big Data Institute, University of Oxford, Oxford, United Kingdom
                [134 ]Geriatric Medicine, Sahlgrenska University Hospital, Mölndal, Sweden
                [135 ]Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
                [136 ]INSERM U-1138, Équipe 2: Pathophysiology and Therapeutics of Vascular and Renal diseases Related to Diabetes, Centre de Recherche des Cordeliers, Paris, France
                [137 ]Department of Endocrinology, Diabetology, Nutrition, and Metabolic Diseases, Bichat Claude Bernard Hospital, Paris, France
                [138 ]Center for Observational Research, Amgen Inc., Thousand Oaks, California, United States of America
                [139 ]Section of Clinical Child and Family Studies, Department of Educational and Family Studies, Vrije Universiteit, Amsterdam, The Netherlands
                [140 ]Dipartimento di Scienze Biomediche, Università degli Studi di Sassari, Sassari, Italy
                [141 ]Department of Medicine I, Ludwig-Maximilians-Universität, Munich, Germany
                [142 ]DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
                [143 ]Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia
                [144 ]Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany
                [145 ]Interdisciplinary Center Psychopathology and Emotion Regulation (ICPE), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
                [146 ]Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
                [147 ]University of Tartu, Estonian Genome Centre, Tartu, Estonia
                [148 ]Genomics of Common Disease, Imperial College London, London, United Kingdom
                [149 ]South Ostrobothnia Central Hospital, Seinäjoki, Finland
                [150 ]Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
                [151 ]Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland
                [152 ]Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana, United States of America
                [153 ]Harvard Medical School, Boston, Massachusetts, United States of America
                [154 ]Social Services and Health Care Department, City of Helsinki, Helsinki, Finland
                [155 ]Division of Research, Kaiser Permanente Northern California, Oakland, California, United States of America
                [156 ]Division of Angiology, Department of Internal Medicine, Medical University Graz, Austria
                [157 ]School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland
                [158 ]LIKES Research Center for Sport and Health Sciences, Jyväskylä, Finland
                [159 ]National Heart and Lung Institute, Imperial College London, United Kingdom
                [160 ]Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
                [161 ]Institute of Nutrition and Functional Foods, Quebec, Canada
                [162 ]School of Nutrition, Laval University, Quebec, Canada
                [163 ]Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Germany
                [164 ]Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
                [165 ]Centre for Population Health Sciences, Usher Institute for Population Health Sciences and Informatics, Teviot Place, Edinburgh, Scotland
                [166 ]MRC Unit for Lifelong Health and Ageing at UCL, London, United Kingdom
                [167 ]Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
                [168 ]Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
                [169 ]Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands
                [170 ]Netherlands Consortium for Healthy Aging, Leiden University Medical Center, Leiden, The Netherlands
                [171 ]Department of Kinesiology, Laval University, Quebec, Canada
                [172 ]Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
                [173 ]University of Leipzig, Medical Department, Leipzig, Germany
                [174 ]Geriatric Unit, Azienda Sanitaria Firenze, Florence, Italy
                [175 ]School of Public Health, University of Adelaide, Adelaide, South Australia, Australia
                [176 ]Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland
                [177 ]Department of Clinical Epidemiology, Bispebjerg and Frederiksberg Hospitals, The Capital Region, Copenhagen, Denmark
                [178 ]Centre for Vascular Prevention, Danube-University Krems, Krems, Austria
                [179 ]Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia
                [180 ]National Institute for Health Research Biomedical Research Centre at Guy's and St. Thomas' Foundation Trust, London, United Kingdom
                [181 ]Department of Clinical Experimental Research, Rigshospitalet, Glostrup, Denmark
                [182 ]Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
                [183 ]Synlab Academy, Synlab Services LLC, Mannheim, Germany
                [184 ]Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
                [185 ]Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany
                [186 ]Department of Epidemiology and Public Health, University College London, London, United Kingdom
                [187 ]Laboratory of Epidemiology and Population Science, National Institute on Aging, Bethesda, Maryland, United States of America
                [188 ]Biocenter Oulu, University of Oulu, Oulu, Finland
                [189 ]MRC-PHE Centre for Environment and Health, Imperial College London, London, United Kingdom
                [190 ]Imperial College Healthcare NHS Trust, London, United Kingdom
                [191 ]Hammersmith Hospital, London, United Kingdom
                [192 ]Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
                [193 ]Wellcome Trust Sanger Institute, Hinxton, United Kingdom
                [194 ]NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, United Kingdom
                [195 ]The University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, United Kingdom
                [196 ]Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, United Kingdom
                [197 ]Oxford NIHR Biomedical Research Centre, Oxford, United Kingdom
                [198 ]Center of Medical Systems Biology, Leiden, The Netherlands
                [199 ]Population Health Research Institute, St. George's University of London, London, United Kingdom
                [200 ]Divisions of Endocrinology and Genetics and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts, United States of America
                [201 ]Department of Public Health & Clinical Medicine, Umeå University, Umeå, Sweden
                [202 ]Carolina Center for Genome Sciences, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
                [203 ]Genetics of Obesity and Related Metabolic Traits Program, Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
                [204 ]The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
                [205 ]The Department of Preventive Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
                Vanderbilt University, UNITED STATES
                Author notes

                We have read the journal's policy and the authors of this manuscript have the following competing interests: Genotyping in the Ely and Fenland studies was supported in part by an MRC-GlaxoSmithKline pilot programme grant (G0701863). The RISC Study was supported in part by AstraZeneca. The D.E.S.I.R. study has been supported in part by INSERM contracts with Lilly, Novartis Pharma, Sanofi-Aventis, Ardix Medical, Bayer Diagnostics, Becton Dickinson, Cardionics, Merck Santé, Novo Nordisk, Pierre Fabre, Roche, and Topcon. In SHIP, genome-wide data have been supported in part by a joint grant from Siemens Healthcare, Erlangen, Germany.

                • Conceptualization: TOK RJFL.

                • Data curation: TOK LAC RJFL KLMon.

                • Formal analysis: RAS KLY AEJ TWW AMa DHa NLHC JSN TSA LQ TW FRe MdH TOK QQ MG TSA LX AYC LAC MC RJFL MFF KEN JDE ADJ JEHa RJK.

                • Investigation: AVS TBH GE LJL VG KEN MG AJ KLMon KLY EB PGL JBW NGM GWM DPS GC LJP JHua AWM ALJ JB MFo CBe HMS TR SSn BS YW JBB LSA ZK PMMV TC SBi GWi PV KKr ASH KHa SM VS MP JM IR CHup VV IK OPo LY DT BB MMar AB PF RRaw TAL PK MHo KSa RMag THal TEb AMa JL RAS SBr NJW JHZ RL SBu AD NA CMvD IBB MFF LB RJFL LX NLHC EL JP PJG CSF CTL LAC MB FSC KLMol RNB JT LK TEs HP CS HAK LFB SLRK MAJ PAP SA FRe IB GH PWF JE CO MLo AEJ JOJ TSA LPa GDS TIAS JEHu DJP SP LJH BHS SSa YCC MFu JRO ARS MHa MA AL HVe LQu THu QQ JAS JDF WZhan DRW KHv OLH AUJ LLB AJS KKv TTan DHe SBa MNH JMJ KF NG OPe TWW IMH MO CG HG AP KSt CHo CHut RRau BT MMN WZhao BL WRS STT JCC JSK MEK GED TBG GS JHui WM UL CHa LL LH KL AGB LJRT JAN YL MLa JK AS PSC NN WJP GvG YM BWJHP AMu CML MIM TTam JA MRJ LQi THan DK KKO AW ÅJ UG EJCdG MHMdM JJH DIB GWa PN AFW NDH SW HC JFW CBo MCV LPe DP MW TMF NVR MCZ FRi AH AGU JLBG SSi FB AMe GRA FC ATe HVo UV MD SG MN RMan IP ATo PJvdM JVvVO IMN HS AJO CAH MMan DIC AYC LMR PMR SBi NZ JG UP CK MKu MKi CL LPL NHK MJ MKä OTR TL.

                • Supervision: GRA IB MB IBB CSF TMF IMH RJFL MIM KLMon KEN JRO DPS CMvD JNH.

                • Writing – original draft: MG RAS AEJ KLY MFF LB LQu PWF RJFL TOK.

                • Writing – review & editing: MG RAS AEJ KLY MFF TWW LB AYC AMa DHa LX TW NLHC TSA MdH QQ JSN FRe LQu JDE JEHa MC ZK EL JL JEHu WZhan WZhao PJG THal SA PMMV SBi LY ATe AVS MKu MNH JMJ MEK MHo NVR JBW JHZ HS LL CHup GWi WJP YW KKr AD KL YL MFo MHa LFB GC TTan RMag PJvdM AUJ JLBG VV JM PN CBe DP ÅJ SSn YCC JE UL MA LSA NA BB JA JB RNB AGB JB AB LLB JBB SBr FB SBu HC PSC FSC TC GDS GED ND MD TEb GE TEs JDF MFu KF CG SG JG PGL HG TBG NG GvG THu KHa NDH ASH DHe LH LJH OLH CHo JJH JHua THan JHui CHut NHK ALJ JOJ MAH MJ LK HAK IK PK JK KKv MKa TAL LJL BL CML MLo RL MMar YM KLMon GWM MHMdM AMu AMe RMan SM NN MN JAN IMN AJO MO KKO SP LPa JP MP AP UP PAP IP HP OTR TR LJRT RRaw PMR LMR IR CS MAS KSa WRS SSa ARS SSi GS BHS JAS HS AS BS AJS TTam STT BT DT LV HVe JVvVO MCV UV GWa MW SW AW AFW MCZ NZ CAHai LL UG CO AH FRi AGU LPe JFW CHa OPo FC KHv CAHar ATo SBa LJP SLRK RRau TIAS JT VS BWJHP EJCdG DIB TL MMan MLa CBo NGM DK AL WM KSt MKi TBH VG HVo LQi MRJ JCC JSK PF CK PV GH OPe NJW CL DRW DJP EB DIC GRA IB MIM TMF JRO CMvD MB IMH KLMol DPS CSF CTL JNH RJK ADJ IBB PWF KEN LAC RJFL TOK.

                ‡ These authors jointly supervised this work.

                ¶ Membership is listed in the Supporting Information.

                Author information
                http://orcid.org/0000-0001-6380-1735
                http://orcid.org/0000-0003-0070-6145
                http://orcid.org/0000-0003-0292-5421
                http://orcid.org/0000-0001-9730-0306
                http://orcid.org/0000-0001-6053-298X
                http://orcid.org/0000-0001-5800-4520
                http://orcid.org/0000-0001-7854-1366
                http://orcid.org/0000-0002-0703-0742
                http://orcid.org/0000-0003-3539-5391
                Article
                PGENETICS-D-16-01816
                10.1371/journal.pgen.1006528
                5407576
                28448500
                b563efdd-c98d-4d3b-b10d-8ee045c084bb

                This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

                History
                : 17 August 2016
                : 7 December 2016
                Page count
                Figures: 1, Tables: 3, Pages: 26
                Funding
                The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services. Funding for this study was provided by the Aase and Ejner Danielsens Foundation; Academy of Finland (102318; 104781, 120315, 123885, 129619, 286284, 134309, 126925, 121584, 124282, 129378, 117787, 250207, 258753, 41071, 77299, 124243, 1114194, 24300796); Accare Center for Child and Adolescent Psychiatry; Action on Hearing Loss (G51); Agence Nationale de la Recherche; Agency for Health Care Policy Research (HS06516); Age UK Research into Ageing Fund; Åke Wiberg Foundation; ALF/LUA Research Grant in Gothenburg; ALFEDIAM; ALK-Abello´ A/S (Hørsholm, Denmark); American Heart Association (13POST16500011, 10SDG269004); Ardix Medical; Arthritis Research UK; Association Diabète Risque Vasculaire; AstraZeneca; Australian Associated Brewers; Australian National Health and Medical Research Council (241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 552485, 552498); Avera Research Institute; Bayer Diagnostics; Becton Dickinson; Biobanking and Biomolecular Resources Research Infrastructure (BBMRI –NL, 184.021.007); Biocentrum Helsinki; Boston Obesity Nutrition Research Center (DK46200); British Heart Foundation (RG/10/12/28456, SP/04/002); Canada Foundation for Innovation; Canadian Institutes of Health Research (FRN-CCT-83028); Cancer Research UK; Cardionics; Center for Medical Systems Biology; Center of Excellence in Complex Disease Genetics and SALVECenter of Excellence in Genomics (EXCEGEN); Chief Scientist Office of the Scottish Government; City of Kuopio; Cohortes Santé TGIR; Contrat de Projets État-Région; Croatian Science Foundation (8875); Danish Agency for Science, Technology and Innovation; Danish Council for Independent Research (DFF–1333-00124, DFF–1331-007308); Danish Diabetes Academy; Danish Medical Research Council; Department of Psychology and Education of the VU University Amsterdam; Diabetes Hilfs- und Forschungsfonds Deutschland; Dutch Brain Foundation; Dutch Ministry of Justice; Emil Aaltonen Foundation; Erasmus Medical Center; Erasmus University; Estonian Government (IUT20-60, IUT24-6); Estonian Ministry of Education and Research (3.2.0304.11-0312); European Commission (230374, 284167, 323195, 692145, FP7 EurHEALTHAgeing-277849, FP7 BBMRI-LPC 313010, nr 602633, HEALTH-F2-2008-201865-GEFOS, HEALTH-F4-2007-201413, FP6 LSHM-CT-2004-005272, FP5 QLG2-CT-2002-01254, FP6 LSHG-CT-2006-01947, FP7 HEALTH-F4-2007-201413, FP7 279143, FP7 201668, FP7 305739, FP6 LSHG-CT-2006-018947, HEALTH-F4-2007-201413, QLG1-CT-2001-01252); European Regional Development Fund; European Science Foundation (EuroSTRESS project FP-006, ESF, EU/QLRT-2001-01254); Faculty of Biology and Medicine of Lausanne; Federal Ministry of Education and Research (01ZZ9603, 01ZZ0103, 01ZZ0403, 03ZIK012, 03IS2061A); Federal State of Mecklenburg - West Pomerania; Fédération Française de Cardiologie; Finnish Cultural Foundation; Finnish Diabetes Association; Finnish Foundation of Cardiovascular Research; Finnish Heart Association; Food Standards Agency; Fondation de France; Fonds Santé; Genetic Association Information Network of the Foundation for the National Institutes of Health; German Diabetes Association; German Federal Ministry of Education and Research (BMBF, 01ER1206, 01ER1507); German Research Council (SFB-1052, SPP 1629 TO 718/2-1); GlaxoSmithKline; Göran Gustafssons Foundation; Göteborg Medical Society; Health and Safety Executive; Heart Foundation of Northern Sweden; Icelandic Heart Association; Icelandic Parliament; Imperial College Healthcare NHS Trust; INSERM, Réseaux en Santé Publique, Interactions entre les déterminants de la santé; Interreg IV Oberrhein Program (A28); Italian Ministry of Economy and Finance; Italian Ministry of Health (ICS110.1/RF97.71); John D and Catherine T MacArthur Foundation; Juho Vainio Foundation; King's College London; Kjell och Märta Beijers Foundation; Kuopio University Hospital; Kuopio, Tampere and Turku University Hospital Medical Funds (X51001); Leiden University Medical Center; Lilly; LMUinnovativ; Lundbeck Foundation; Lundberg Foundation; Medical Research Council of Canada; MEKOS Laboratories (Denmark); Merck Santé; Mid-Atlantic Nutrition Obesity Research Center (P30 DK72488); Ministère de l’Économie, de l’Innovation et des Exportations; Ministry for Health, Welfare and Sports of the Netherlands; Ministry of Cultural Affairs of the Federal State of Mecklenburg-West Pomerania; Ministry of Education and Culture of Finland (627;2004-2011); Ministry of Education, Culture and Science of the Netherlands; MRC Human Genetics Unit; MRC-GlaxoSmithKline Pilot Programme Grant (G0701863); Municipality of Rotterdam; Netherlands Bioinformatics Centre (2008.024); Netherlands Consortium for Healthy Aging (050-060-810); Netherlands Genomics Initiative; Netherlands Organisation for Health Research and Development (904-61-090, 985-10-002, 904-61-193, 480-04-004, 400-05-717, Addiction-31160008, Middelgroot-911-09-032, Spinozapremie 56-464-14192); Netherlands Organisation for Health Research and Development (2010/31471/ZONMW); Netherlands Organisation for Scientific Research (10-000-1002, GB-MW 940-38-011, 100-001-004, 60-60600-97-118, 261-98-710, GB-MaGW 480-01-006, GB-MaGW 480-07-001, GB-MaGW 452-04-314, GB-MaGW 452-06-004, 175.010.2003.005, 175.010.2005.011, 481-08-013, 480-05-003, 911-03-012); Neuroscience Campus Amsterdam; NHS Foundation Trust; Novartis Pharmaceuticals; Novo Nordisk; Office National Interprofessionel des Vins; Paavo Nurmi Foundation; Påhlssons Foundation; Päivikki and Sakari Sohlberg Foundation; Pierre Fabre; Republic of Croatia Ministry of Science, Education and Sport (108-1080315-0302); Research Centre for Prevention and Health, the Capital Region for Denmark; Research Institute for Diseases in the Elderly (014-93-015, RIDE2); Roche; Russian Foundation for Basic Research (NWO-RFBR 047.017.043); Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06); Sanofi-Aventis; Scottish Executive Health Department (CZD/16/6); Siemens Healthcare; Social Insurance Institution of Finland (4/26/2010); Social Ministry of the Federal State of Mecklenburg-West Pomerania; Société Francophone du Diabète; State of Bavaria; Stroke Association; Swedish Diabetes Association; Swedish Foundation for Strategic Research; Swedish Heart-Lung Foundation (20140543); Swedish Research Council (2015-03657); Swedish Medical Research Council (K2007-66X-20270-01-3, 2011-2354); Swedish Society for Medical Research; Swiss National Science Foundation (33CSCO-122661, 33CS30-139468, 33CS30-148401); Tampere Tuberculosis Foundation; The Marcus Borgström Foundation; The Royal Society; The Wellcome Trust (084723/Z/08/Z, 088869/B/09/Z); Timber Merchant Vilhelm Bangs Foundation; Topcon; Torsten and Ragnar Söderberg's Foundation; UK Department of Health; UK Diabetes Association; UK Medical Research Council (MC_U106179471, G0500539, G0600705, G0601966, G0700931, G1002319, K013351, MC_UU_12019/1); UK National Institute for Health Research BioResource Clinical Research Facility and Biomedical Research Centre; UK National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre; UK National Institute for Health Research (RP-PG-0407-10371); Umeå University Career Development Award; United States – Israel Binational Science Foundation Grant (2011036); University Hospital Oulu (75617); University Medical Center Groningen; University of Tartu (SP1GVARENG); National Institutes of Health (AG13196, CA047988, HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSC271201100004C, HHSN268200900041C, HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, HHSN268201500001I, HL36310, HG002651, HL034594, HL054457, HL054481, HL071981, HL084729, HL119443, HL126024, N01-AG12100, N01-AG12109, N01-HC25195, N01-HC55015, N01-HC55016, N01-HC55018, N01-HC55019, N01-HC55020, N01-HC55021, N01-HC55022, N01-HD95159, N01-HD95160, N01-HD95161, N01-HD95162, N01-HD95163, N01-HD95164, N01-HD95165, N01-HD95166, N01-HD95167, N01-HD95168, N01-HD95169, N01-HG65403, N02-HL64278, R01-HD057194, R01-HL087641, R01-HL59367, R01HL-086694, R01-HL088451, R24-HD050924, U01-HG-004402, HHSN268200625226C, UL1-RR025005, UL1-RR025005, UL1-TR-001079, UL1-TR-00040, AA07535, AA10248, AA11998, AA13320, AA13321, AA13326, AA14041, AA17688, DA12854, MH081802, MH66206, R01-D004215701A, R01-DK075787, R01-DK089256, R01-DK8925601, R01-HL088451, R01-HL117078, R01-DK062370, R01-DK072193, DK091718, DK100383, DK078616, 1Z01-HG000024, HL087660, HL100245, R01DK089256, 2T32HL007055-36, U01-HL072515-06, U01-HL84756, NIA-U01AG009740, RC2-AG036495, RC4-AG039029, R03 AG046389, 263-MA-410953, 263-MD-9164, 263-MD-821336, U01-HG004802, R37CA54281, R01CA63, P01CA33619, U01-CA136792, U01-CA98758, RC2-MH089951, MH085520, R01-D0042157-01A, MH081802, 1RC2-MH089951, 1RC2-MH089995, 1RL1MH08326801, U01-HG007376, 5R01-HL08767902, 5R01MH63706:02, HG004790, N01-WH22110, U01-HG007033, UM1CA182913, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221); USDA National Institute of Food and Agriculture (2007-35205-17883); Västra Götaland Foundation; Velux Foundation; Veterans Affairs (1 IK2 BX001823); Vleugels Foundation; VU University’s Institute for Health and Care Research (EMGO+, HEALTH-F4-2007-201413) and Neuroscience Campus Amsterdam; Wellcome Trust (090532, 091551, 098051, 098381); Wissenschaftsoffensive TMO; and Yrjö Jahnsson Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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