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      The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study

      research-article
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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          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, WHR adjBMI), 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 WHR adjBMI, 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 WHR adjBMI 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 WHR adjBMI, 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 WHR adjBMI. 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 WHR adjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.

          Author Summary

          Adult body size and body shape differ substantially between men and women and change over time. More than 100 genetic variants that influence body mass index (measure of body size) or waist-to-hip ratio (measure of body shape) have been identified. While there is evidence that some genetic loci affect body shape differently in men than in women, little is known about whether genetic effects differ in older compared to younger adults, and whether such changes differ between men and women. Therefore, we conducted a systematic genome-wide search, including 114 studies (>320,000 individuals), to specifically identify genetic loci with age- and or sex-dependent effects on body size and shape. We identified 15 loci of which the effect on BMI was different in older compared to younger adults, whereas we found no evidence for loci with different effects in men compared to women. The opposite was seen for body shape as we identified 44 loci of which the effect on waist-to-hip ratio differed between men and women, but no difference between younger and older adults were observed. Our observations may provide new insights into the biology that underlies weight change with age or the sexual dimorphism of body shape.

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          Most cited references97

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          • Abstract: found
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          PLINK: a tool set for whole-genome association and population-based linkage analyses.

          Whole-genome association studies (WGAS) bring new computational, as well as analytic, challenges to researchers. Many existing genetic-analysis tools are not designed to handle such large data sets in a convenient manner and do not necessarily exploit the new opportunities that whole-genome data bring. To address these issues, we developed PLINK, an open-source C/C++ WGAS tool set. With PLINK, large data sets comprising hundreds of thousands of markers genotyped for thousands of individuals can be rapidly manipulated and analyzed in their entirety. As well as providing tools to make the basic analytic steps computationally efficient, PLINK also supports some novel approaches to whole-genome data that take advantage of whole-genome coverage. We introduce PLINK and describe the five main domains of function: data management, summary statistics, population stratification, association analysis, and identity-by-descent estimation. In particular, we focus on the estimation and use of identity-by-state and identity-by-descent information in the context of population-based whole-genome studies. This information can be used to detect and correct for population stratification and to identify extended chromosomal segments that are shared identical by descent between very distantly related individuals. Analysis of the patterns of segmental sharing has the potential to map disease loci that contain multiple rare variants in a population-based linkage analysis.
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            • Record: found
            • Abstract: found
            • Article: found
            Is Open Access

            ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data

            High-throughput sequencing platforms are generating massive amounts of genetic variation data for diverse genomes, but it remains a challenge to pinpoint a small subset of functionally important variants. To fill these unmet needs, we developed the ANNOVAR tool to annotate single nucleotide variants (SNVs) and insertions/deletions, such as examining their functional consequence on genes, inferring cytogenetic bands, reporting functional importance scores, finding variants in conserved regions, or identifying variants reported in the 1000 Genomes Project and dbSNP. ANNOVAR can utilize annotation databases from the UCSC Genome Browser or any annotation data set conforming to Generic Feature Format version 3 (GFF3). We also illustrate a ‘variants reduction’ protocol on 4.7 million SNVs and indels from a human genome, including two causal mutations for Miller syndrome, a rare recessive disease. Through a stepwise procedure, we excluded variants that are unlikely to be causal, and identified 20 candidate genes including the causal gene. Using a desktop computer, ANNOVAR requires ∼4 min to perform gene-based annotation and ∼15 min to perform variants reduction on 4.7 million variants, making it practical to handle hundreds of human genomes in a day. ANNOVAR is freely available at http://www.openbioinformatics.org/annovar/ .
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              GCTA: a tool for genome-wide complex trait analysis.

              For most human complex diseases and traits, SNPs identified by genome-wide association studies (GWAS) explain only a small fraction of the heritability. Here we report a user-friendly software tool called genome-wide complex trait analysis (GCTA), which was developed based on a method we recently developed to address the "missing heritability" problem. GCTA estimates the variance explained by all the SNPs on a chromosome or on the whole genome for a complex trait rather than testing the association of any particular SNP to the trait. We introduce GCTA's five main functions: data management, estimation of the genetic relationships from SNPs, mixed linear model analysis of variance explained by the SNPs, estimation of the linkage disequilibrium structure, and GWAS simulation. We focus on the function of estimating the variance explained by all the SNPs on the X chromosome and testing the hypotheses of dosage compensation. The GCTA software is a versatile tool to estimate and partition complex trait variation with large GWAS data sets.
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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
                1 October 2015
                October 2015
                : 11
                : 10
                : e1005378
                Affiliations
                [1 ]Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University Regensburg, Regensburg, Germany
                [2 ]Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
                [3 ]Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, United States of America
                [4 ]Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, United States of America
                [5 ]Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, United States of America
                [6 ]Divisions of Endocrinology and Genetics and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts, United States of America
                [7 ]Estonian Genome Center, Univeristy of Tartu, Tartu, Estonia
                [8 ]Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America
                [9 ]Science for Life Laboratory, Uppsala University, Uppsala, Sweden
                [10 ]Department of Medical Sciences, Molecular Epidemiology, Uppsala University, Uppsala, Sweden
                [11 ]Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
                [12 ]MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
                [13 ]The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
                [14 ]The Department of Preventive Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
                [15 ]Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
                [16 ]Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America
                [17 ]Swiss Institute of Bioinformatics, Lausanne, Switzerland
                [18 ]Institute of Social and Preventive Medicine, University Hospital Lausanne (CHUV), Lausanne, Switzerland
                [19 ]Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
                [20 ]Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
                [21 ]Department of Specialties of Internal Medicine, Geneva University Hospital, Geneva, Switzerland
                [22 ]Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
                [23 ]Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, United States of America
                [24 ]National Heart, Lung, and Blood Institute, the Framingham Heart Study, Framingham, Massachusetts, United States of America
                [25 ]University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
                [26 ]Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, United Kingdom
                [27 ]Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
                [28 ]Hammersmith Hospital, London, United Kingdom
                [29 ]Department of Genomics of Common Diseases, School of Public Health, Imperial College London, London, United Kingdom
                [30 ]Division of Biostatistics, Washington University School of Medicine, St. Louis, Missouri, United States of America
                [31 ]Department of Psychiatry and EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, the Netherlands
                [32 ]Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America
                [33 ]Divisions of Genetics and Rheumatology, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, United States of America
                [34 ]Partners Center for Personalized Genetic Medicine, Boston, Massachusetts, United States of America
                [35 ]Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America
                [36 ]HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, United States of America
                [37 ]Steno Diabetes Center A/S, Gentofte, Denmark
                [38 ]COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
                [39 ]Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Skåne University Hospital Malmö, Malmö, Sweden
                [40 ]Institute of Genetic Epidemiology, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg, Germany
                [41 ]Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPA) Centre for Environment and Health, School of Public Health, Imperial College, London, United Kingdom
                [42 ]Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands
                [43 ]Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, United States of America
                [44 ]Department of Medicine, University of Washington, Seattle, Washington, United States of America
                [45 ]CNRS UMR 8199, Lille, France
                [46 ]European Genomic Institute for Diabetes, Lille, France
                [47 ]Université de Lille 2, Lille, France
                [48 ]Montreal Heart Institute, Montréal, Québec, Canada
                [49 ]Centre for Genetic Origins of Health and Disease, University of Western Australia, Crawley, Western Australia, Australia
                [50 ]VA Maryland Health Care System, Baltimore, Maryland, United States of America
                [51 ]University of Maryland School of Medicine, Department of Medicine, Baltimore, Maryland, United States of America
                [52 ]Department of Ecology and Evolutionary Biology, University of California, Los Angeles, Los Angeles, California, United States of America
                [53 ]Vth Department of Medicine, Mannheim Medical Faculty, University of Heidelberg, Mannheim, Germany
                [54 ]Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands
                [55 ]Universiy of Maryland School of Medicine, Department of Epidemiology & Public Health, Baltimore, Maryland, United States of America
                [56 ]National Institute for Health and Welfare, Department of Chronic Disease Prevention, Helsinki, Finland
                [57 ]National Institute for Health and Welfare, Public Health Genomics Unit, Helsinki, Finland
                [58 ]Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
                [59 ]Icelandic Heart Association, Kopavogur, Iceland
                [60 ]Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
                [61 ]Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
                [62 ]Department of Health Sciences, University of Milan, Milan, Italy
                [63 ]Filarete Foundation, Genomic and Bioinformatics Unit, Milano, Italy
                [64 ]Radboud university medical center, Radboud Institute for Health Sciences, Department for Health Evidence, Nijmegen, The Netherlands
                [65 ]Division of Cardiovacular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
                [66 ]Department of Nephrology, University Hospital Regensburg, Regensburg, Germany
                [67 ]Experimental Cardiology and laboratory of clinical chemistry, UMCU, Utrecht, The Netherlands
                [68 ]Department of Biological Psychology, VU University, Amsterdam, The Netherlands
                [69 ]MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland
                [70 ]Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
                [71 ]Core Genotyping Facility, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland, United States of America
                [72 ]Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
                [73 ]Institute of Health Sciences, University of Oulu, Oulu, Finland
                [74 ]Folkhälsan Research Centre, Helsinki, Finland
                [75 ]Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland
                [76 ]University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, Netherlands
                [77 ]Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom
                [78 ]Thurston Arthritis Research Center, University of North Carolina at Chapel Hill, Chaper Hill, North Carolina, United States of America
                [79 ]Washington University Medical School, St. Louis, Missouri, United States of America
                [80 ]Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom
                [81 ]Program in Biostatistics and Biomathematics, Divison of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
                [82 ]Department of Biostatistics, University of Washington, Seattle, Washington, United States of America
                [83 ]Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), The Netherlands
                [84 ]Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands
                [85 ]Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
                [86 ]The Center for Observational Research, Amgen Inc., Thousand Oaks, California, United States of America
                [87 ]Program for Personalized and Genomic Medicine, Division of Endocrinology, Diabetes & Nutrition, Dept of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States of America
                [88 ]Center for Evidence Based Healthcare, University of Dresden, Medical Faculty Carl Gustav Carus, Dresden, Germany
                [89 ]Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany
                [90 ]Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany
                [91 ]DZHK (German Centre for Cardiovascular Research), partnersite Munich Heart Alliance, Munich, Germany
                [92 ]University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, The Netherlands
                [93 ]Wellcome Trust Sanger Institute, Human Genetics, Hinxton, Cambridge, United Kingdom
                [94 ]Institute of Cell & Molecular Biosciences, Newcastle University, Newcastle, United Kingdom
                [95 ]MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom
                [96 ]Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America
                [97 ]Istituto di Ricerca Genetica e Biomedica, CNR, Monserrato, Italy
                [98 ]Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
                [99 ]National Cancer Institute, Bethesda, Maryland, United States of America
                [100 ]Faculty of Medicine, University of Iceland, Reykjavik, Iceland
                [101 ]Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
                [102 ]deCODE Genetics, Amgen inc., Reykjavik, Iceland
                [103 ]Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
                [104 ]Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden
                [105 ]Translational Gerontology Branch, National Institute on Aging, Baltimore, Maryland, United States of America
                [106 ]Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
                [107 ]Institute of Cell and Molecular Biology, Department of Biotechnology, University of Tartu, Tartu, Estonia
                [108 ]University of Helsinki, Helsinki, Finland
                [109 ]Department of Oncology, University of Cambridge, Cambridge, United Kingdom
                [110 ]Department of Internal Medicine, Section of Geriatric Medicine, Academic Medical Center, Amsterdam, The Netherlands
                [111 ]Department of Medical Genetics, University Medical Center Utrecht, Utrecht, Netherlands
                [112 ]University of Groningen, University Medical Center Groningen, Department of Endocrinology, Groningen, The Netherlands
                [113 ]Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland
                [114 ]Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, United States of America
                [115 ]Divisions of Genetics and Endocrinology and Program in Genomics, Boston's Children's Hospital, Boston, Massachusetts, United States of America
                [116 ]Centre for Population Health Sciences, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland
                [117 ]DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Lübeck, Germany
                [118 ]Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, Lübeck, Germany
                [119 ]Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland
                [120 ]MRC Unit for Lifelong Health & Ageing at UCL, London, United Kingdom
                [121 ]Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia
                [122 ]Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, United States of America
                [123 ]Ealing Hospital NHS Trust, Middlesex, United Kingdom
                [124 ]University of Groningen, University Medical Center Groningen, Department of Medicine, Groningen, Netherlands
                [125 ]Centro Cardiologico Monzino, IRCCS, Milan, Italy
                [126 ]Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Milan, Italy
                [127 ]Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas, United States of America
                [128 ]Genomics Research Centre, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia
                [129 ]Department of Pediatrics, University of California San Diego, La Jolla, California, United States of America
                [130 ]Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
                [131 ]University of Leipzig, IFB Adiposity Diseases, Leipzig, Germany
                [132 ]University of Leipzig, Department of Medicine, Leipzig, Germany
                [133 ]University Rennes 1, Rennes, France
                [134 ]Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, United States of America
                [135 ]University of Groningen, University Medical Center Groningen, The LifeLines Cohort Study, Groningen, The Netherlands
                [136 ]Los Angeles BioMedical Resesarch Institute at Harbor-UCLA Medical Center, Torrance, California, United States of America
                [137 ]Department of Internal Medicine I, Ulm University Medical Centre, Ulm, Germany
                [138 ]Universiy of Maryland School of Medicine, Department of Neurology, Baltimore, Maryland, United States of America
                [139 ]EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands
                [140 ]Department of Human Nutrition, Wageningen University, Wageningen, The Netherlands
                [141 ]Department of Dietetics-Nutrition, Harokopio University, Athens, Greece
                [142 ]NorthShore University HealthSystem, Evanston, Illinois, United States of America
                [143 ]University of Chicago, Chicago, Illinois, United States of America
                [144 ]Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece
                [145 ]Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany
                [146 ]Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
                [147 ]Hypertension and Related Disease Centre, AOU-University of Sassari, Sassari, Italy
                [148 ]Kaiser Permanente, Division of Research, Oakland, California, United States of America
                [149 ]The Department of Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
                [150 ]Department of Medicine III, Pathobiochemistry, University of Dresden, Dresden, Germany
                [151 ]Research Unit of Molecular Epidemiology, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg, Germany
                [152 ]Institute of Epidemiology II, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg, Germany
                [153 ]German Center for Diabetes Research (DZD), Neuherberg, Germany
                [154 ]Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium
                [155 ]Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
                [156 ]Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, Maryland, United States of America
                [157 ]National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America
                [158 ]University of Groningen, University Medical Center Groningen, Department of Psychiatry, Groningen, The Netherlands
                [159 ]Kuopio Research Institute of Exercise Medicine, Kuopio, Finland
                [160 ]Institue of Biomedical & Clinical Science, University of Exeter, Exeter, United Kingdom
                [161 ]QIMR Bergofer Medical Research Institute, Brisbane, Queensland, Australia
                [162 ]Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America
                [163 ]Department of Public Health and General Practice, Norwegian University of Science and Technology, Trondheim, Norway
                [164 ]Department Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands
                [165 ]Pathwest Laboratory Medicine of Western Australia, Nedlands, Western Australia,Australia
                [166 ]School of Pathology and Laboratory Medicine, University of Western Australia, Nedlands, Western Australia, Australia
                [167 ]School of Population Health, University of Western Australia, Nedlands, Western Australia, Australia
                [168 ]Research Centre for Prevention and Health, Glostrup Hospital, Glostrup, Denmark
                [169 ]Department of Pediatrics, University of Tampere School of Medicine, Tampere, Finland
                [170 ]Department of Pediatrics,Tampere University Hospital, Tampere, Finland
                [171 ]Hannover Unified Biobank, Hannover Medical School, Hannover, Germany
                [172 ]Institute of Human Genetics, Hannover Medical School, Hanover, Germany
                [173 ]Harvard Medical School, Boston, Massachusetts,United States of America
                [174 ]Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts,United States of America
                [175 ]Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
                [176 ]Faculty of Medicine, University of Aalborg, Aalborg, Denmark
                [177 ]Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands
                [178 ]Division of Medicine, Turku University Hospital, Turku, Finland
                [179 ]Murdoch Children's Research Institute, Parkville, Victoria, Australia
                [180 ]Department of Medicine, University of Turku, Turku, Finland
                [181 ]William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
                [182 ]Echinos Medical Centre, Echinos, Greece
                [183 ]Clinical Gerontology Unit, Addenbrooke's Hospital, Cambridge, United Kingdom
                [184 ]Department of Health, National Institute for Health and Welfare, Helsinki, Finland
                [185 ]Department of Internal Medicine II—Cardiology, University of Ulm Medical Center, Ulm, Germany
                [186 ]Department of Public Health, Faculty of Medicine, University of Split, Split, Croatia
                [187 ]Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
                [188 ]Department of Epidemiology and Public Health, UCL, London, United Kingdom
                [189 ]Department of Public Health and Caring Sciences, Geriatrics, Uppsala University, Uppsala, Sweden
                [190 ]Chair of Nephrology, Università Vita Salute San Raffaele, Segrate (Milan), Italy
                [191 ]Genomics of Renal Disease and Hypertension Unit, IRCCS San Raffaele Scientific Institute, Segrate (Milan), Italy
                [192 ]Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada
                [193 ]Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland
                [194 ]Department of Clinical Experimental Research, Rigshospitalet, Glostrup, Denmark
                [195 ]Strangeways Research Laboratory Wort's Causeway, Cambridge, United Kingdom
                [196 ]Lund University Diabetes Centre and Department of Clinical Science, Diabetes & Endocrinology Unit, Lund University, Malmö, Sweden
                [197 ]Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
                [198 ]School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom
                [199 ]Department of Biostatistics, University of Liverpool, Liverpool, United Kingdom
                [200 ]Department of Paediatrics, University of Cambridge, Cambridge, United Kingdom
                [201 ]Massachusetts General Hospital, Center for Human Genetic Research, Psychiatric and Neurodevelopmental Genetics Unit, Boston, Massachusetts, United States of America
                [202 ]Department of Kinesiology, Laval University, Québec City, Québec, Canada
                [203 ]Institute of Nutrition and Functional Foods, Laval University, Québec City, Québec, Canada
                [204 ]Center for Biomedicine, European Academy Bozen/Bolzano (EURAC), Bolzano, Italy, Affiliated Institute of the University of Lübeck, Lübeck, Germany
                [205 ]Department of Children, Young People and Families, National Institute for Health and Welfare, Helsinki, Finland
                [206 ]Department of Obstetrics and Gynecology, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
                [207 ]Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, United States of America
                [208 ]Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana, United States of America
                [209 ]Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden
                [210 ]Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
                [211 ]Department of Medical Sciences, Uppsala University, Uppsala, Sweden
                [212 ]National Heart and Lung Institute, Imperial College London, London, United Kingdom
                [213 ]Anogia Medical Centre, Anogia, Greece
                [214 ]DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany
                [215 ]School of Nutrition, Laval University, Québec City, Québec,Canada
                [216 ]Department of Clinical Chemistry, Ulm University Medical Centre, Ulm, Germany
                [217 ]Department of Clinical Medicine, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway
                [218 ]Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway
                [219 ]VUMC, Department of Epidemiology and Biostatistics, Amsterdam, The Netherlands
                [220 ]Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, Netherlands
                [221 ]Durrer Center for Cardiogenetic Research, Interuniversity Cardiology Institute Netherlands-Netherlands Heart Institute, Utrecht, The Netherlands
                [222 ]Institute of Cardiovascular Science, University College London, London, United Kingdom
                [223 ]Department of Epidemiology, University Medical Center, Utrecht, The Netherlands
                [224 ]Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America
                [225 ]Imperial College London, London, United Kingdom
                [226 ]Lee Kong Chian School of Medicine, Singapore, Singapore
                [227 ]Nanyang Technological University, Singapore, Singapore
                [228 ]Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center, Houston, Texas, United States of America
                [229 ]Department of Medicine III, University of Dresden, Medical Faculty Carl Gustav Carus, Dresden, Germany
                [230 ]Imperial College Healthcare NHS Trust, London, United Kingdom
                [231 ]University of Sassari, Sassari, Italy
                [232 ]Institute of Biomedical Technologies, National Institute of Research, Segrate-Milano, Italy
                [233 ]Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland
                [234 ]Rush Institute for Healthy Aging and Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, United States of America
                [235 ]Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands
                [236 ]Robertson Center for Biostatistics, University of Glasgow, Glasgow, United Kingdom
                [237 ]Department of Public Health & Clinical Medicine, Umeå University Hospital, Umeå, Sweden, Umeå, Sweden
                [238 ]Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, United States of America
                [239 ]Department of Medicine, Karolinska Institutet, Stockholm, Sweden
                [240 ]Deutsches Herzzentrum München, Technische Universität München, München, Germany
                [241 ]Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, United States of America
                [242 ]Medical Research Center Oulu, Oulu University Hospital, and University of Oulu, Oulu, Finland
                [243 ]Department of Pulmonary Physiology and Sleep Medicine, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia
                [244 ]Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland
                [245 ]Department of Clinical Physiology, University of Tampere School of Medicine, Tampere, Finland
                [246 ]Children's Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
                [247 ]Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, United States of America
                [248 ]Center for Human Genetics Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America
                [249 ]Radboud university medical center, Radboud Institute for Health Sciences, Department of Urology, Nijmegen, The Netherlands
                [250 ]National Institute for Health and Welfare, Helsinki, Finland
                [251 ]University of Helsinki and Helsinki University Central Hospital, Department of Medicine and Abdominal Center: Endocrinology, Helsinki, Finland
                [252 ]Minerva Foundation Institute for Medical Research, Helsinki, Finland
                [253 ]Department of Physiology, Institute of Biomedicine, University of Eastern Finland, Kuopio Campus, Kuopio, Finland
                [254 ]Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere, Finland
                [255 ]Department of Clinical Chemistry, Fimlab Laboratories and School of Medicine, University of Tampere, Tampere, Finland
                [256 ]Department of Medicine, Université de Montréal, Montréal, Québec, Canada
                [257 ]Stanford University, Stanford, California, United States of America
                [258 ]Primary Health Care Unit, Institute of Public Health and Clinical Nutrition, School of Medicine, University of Eastern Finland, Kuopio, Finland
                [259 ]Primary Health Care Unit, Kuopio University Hospital, Kuopio, Finland
                [260 ]Department of Medicine, Stanford University School of Medicine, Stanford, California, United States of America
                [261 ]Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, Maryland, United States of America
                [262 ]Department of Surgery, University Medical Center Utrecht, Utrecht, Netherlands
                [263 ]Department of Pediatrics, University of Iowa, Iowa City, Iowa, United States of America
                [264 ]Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia
                [265 ]HUCH Heart and Lung Center, Division of Cardiology, Helsinki University Central Hospital, Helsinki, Finland
                [266 ]University of Groningen, University Medical Center, Interdisciplinary Center Psychopathology and Emotion Regulation, Groningen, The Netherlands
                [267 ]School of Public Health, University of Adelaide, Adelaide, South Australia, Australia
                [268 ]Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia
                [269 ]Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota, United States of America
                [270 ]Department of Neurology, General Central Hospital, Bolzano, Italy
                [271 ]Departments of Epidemiology and Health Services, University of Washington, Seattle, Washington, United States of America
                [272 ]Group Health Research Institute, Group Health Cooperative, Seatte, Washington, United States of America
                [273 ]Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
                [274 ]Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland
                [275 ]Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland
                [276 ]Department of Medicine, Central Finland Central Hospital, Jyväskylä, Finland
                [277 ]BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
                [278 ]Geriatric Research and Education Clinical Center, Vetrans Administration Medical Center, Baltimore, Maryland, United States of America
                [279 ]MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom
                [280 ]Institute of Preventive Medicine, Bispebjerg and Frederiksberg Hospital, The Capital Region, Frederiksberg, Denmark
                [281 ]R & D VitaK Group, Maastricht University, Maastricht, The Netherlands
                [282 ]Geriatric Unit, Azienda Sanitaria Firenze (ASF), Florence, Italy
                [283 ]Faculty of Medicine, University of Iceland, Reykjavik, Iceland
                [284 ]Centre for Vascular Prevention, Danube-University Krems, Krems, Austria
                [285 ]Instituto de Investigacion Sanitaria del Hospital Universitario La Paz (IdiPAZ), Madrid, Spain
                [286 ]Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia
                [287 ]Department of Public Health and Clinical Nutrition, University of Eastern Finland, Finland
                [288 ]Research Unit, Kuopio University Hospital, Kuopio, Finland
                [289 ]Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands
                [290 ]Department of Internal Medicine, University Hospital Lausanne (CHUV) and University of Lausanne, Lausanne, Switzerland
                [291 ]Institute of Cellular Medicine, Newcastle University, Newcastle, United Kingdom
                [292 ]The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium
                [293 ]The DIAbetes Genetics Replication And Meta-analysis Consortium
                [294 ]The Global Lipids Genetics Consortium
                [295 ]The Global Blood Pressure Genetics Consortium
                [296 ]The International Consortium for Blood Pressure
                [297 ]The Meta-Analyses of Glucose and Insulin-related traits Consortium
                [298 ]Department of Nutrition, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, United States of America
                [299 ]Carolina Population Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
                [300 ]National Heart, Lung, and Blood Institute, National Institute of Health, Bethesda, Maryland, United States of America
                [301 ]NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science Addenbrooke’s Hospital, Cambridge, United Kingdom
                [302 ]University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science Addenbrooke’s Hospital, Cambridge, United Kingdom
                [303 ]Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia
                [304 ]Finnish Institute for Molecular Medicine (FIMM), Helsinki University, Helsinki, Finland
                [305 ]Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America
                [306 ]Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, United States of America
                [307 ]Department of Epidemiology and Popualtion Health, Albert Einstein College of Medicine, Bronx, New York, United States of America
                [308 ]Oxford NIHR Biomedical Research Centre, Oxford, United Kingdom
                [309 ]Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, United States of America
                [310 ]Population Health Research Institute, St George's, University of London, London, United Kingdom
                [311 ]Center for Medical Systems Biology, Leiden, The Netherlands
                [312 ]Carolina Center for Genome Sciences and Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
                [313 ]The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
                [314 ]The Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
                National Institute of Health, National Human Genome Research Institute, UNITED STATES
                Author notes

                I have read the journals policy and we have the following conflicts: KSte, UT, VSte and GT are employed by deCODE Genetics/Amgen inc. IB and spouse own stock in Incyte Ltd and GlaxoSmithKline. JMJ serves as consultant for Trinity Partners, Inc., Samumed, Flexion, and is deputy editor for Osteoarthritis & Cartilage and serves on board of directors of American College of Rheumatology. PV and GWa received an unresticted grant from GlaxoSmithKline to build the CoLaus study. BMP serves on the data and safety monitoring board (DSMB) for a clinical trial of a device funded by the manufacturer (Zoll LifeCor) and serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson.

                Conceived and designed the experiments: IBB IMH KEN RJFL TWW ZK. Performed the experiments: AEJ LBa MGr TWW ZK. Analyzed the data: AEJ LBa MGr RM TWW ZK. Contributed reagents/materials/analysis tools: AEJ LBa MGr TWW ZK. Wrote the paper: AEJ IBB IMH KEN LBa MGr MFF RJFL TWW ZK. Contributed genome-wide association study results: AAH AB ACA ACHa ACHe ACS AD AEF AEJ AFW AG AGU AHa AHo AJ ÅJ AJMdC AJO AJS AKH ALJ ALMV AMa AMe APa APe APM APo ARSa ARSh ASB ASG ASt ATe ATH ATö ATr AUJ AVS AWM BAO BDM BF BL BMK BMP BOB BSt BT BWP CAB CAH CBa CBe CBo CG CHa CHe CLang CM CMG CML CMvD CO CR CSF CW CWKC DA DAB DAE DC DCR DFL DH DIB DIC DJH DPS DS EA EB EE EI EJCdG EK EM EPB ETs EV EW EZ FB FC FF FG FH FLM FRe FRiv FRiz FSC FWA GB GC GDed GDel GE GL GM GP GRA GT GWa GWi GWM HAB HAK HC HGra HGrö HH HMdR HMS HScha HSchu HSn HV HVH HWal HWat IB IBB IF IK IMH IML IMN IN IPi IPr IR IT JAS JBe JBl JCB JCC JCM JCo JCT JCz JD JDR JEH JErd JEri JFW JG JGE JH JHS JHZ JIR JJH JKr JKu JLa JLBG JLu JMJ JMV JNH JPT JROC JSB JSh JSin JSK JSP JSV JT JvS JVvVO JWJ JY KAR KBJ KEN KKO KLMoh KLMon KMR KP KSL KSte KSti KTK LAC LALMK LBa LBr LCG LCPGMdG LFe LJL LJP LK LLa LLi LLW LM LMR LMYA LPas LPat LPé LQ LS LV LYe LYu MASa MASw MBa MBl MBo MBr MCV MCZ MD MEK MEM MF MFF MGo MGP MGr MHa MHe MJ MKä MKaa MKar MLa MLL MLo MMa MMe MN MP MRh MS MSN MWald MWalk ND NE NF NGl NGM NH NHK NJW NLHC NLP NMvS NP NS NV NvdV NWR OG OPo OTR PAFM PB PBK PD PEHS PES PF PGH PH PIWdB PJvdM PK PKM PLdJ PMR PPP PS PSC PV PvdH PVG PWF RAS RJFL RL RM RNB RPS RR RTG RWW SA SB SCvD SE SG SH SHV SHW SIB SJ SJC SJK SJLB SKan SKat SKo SL SMä SRB SRW SSa SSc SSeb ST STT SWvdL TAL TBG TBH TDS TE TEG TFa TH TIAS TK TKR TL TLA TMT TQ TR TSA TT TW UG UT UV VG VLo VLy VSa VSt VV WLMA WM WRS WZ YCC YDIC YJS YLi YLu YMG YPL ZK ZW. Contributed Metabochip association study results: AB AHa AHi AL AMe ASi AW BG BOB BSe CLang CLanz DB DK EAA EE EI EM ETr FB FRe IB IMH JHZ JLi JLu JSa KB KF KGH KH KKO KL KSti KTK LLB LLH LM LYe MGo MKi MKu MMN MRi MU NGF NGr NJW NLP NN NTK OH OPe PD PF PM PWF RAS RJFL RJS RL RRM RW SA SCB SKan SL SMe TE TFa TH THS TI TJ TS TSA TWW UdF WKo WKr. Contributed SNP look-up data: AC CCW CEJ DCR GBE IPr JSim LAC NLHC RM SSen TFe VLa. Performed Study-specific GCTA analyses: ATe MGr SR TE TWW ZK. Performed study-specific quality control: AEJ JCz LBa MFF MGr RM SC TE TFa TOK TWW YLu ZK. Performed DEPICT Gene Pathway analyses: JKa JNH LFr THP. Performed IPA Gene Pathway analyses: AEJ. Performed Expression Quantitative trait loci (eQTL) analyses: HJW LFr RJ TE. Performed Mouse microarray expression analyses: DJC MDN. Contributed Look-up information and analyses for young adults ages 16–25 years: KEN LAC MGr PGL SIB. GIANT Steering committee: CMvD CSF DJH DPS DS EI GRA IB IBB IMH JNH JROC KEN KLMoh LCG MBo MIMC PD RCK RJFL SIB TLA UT.

                ‡ These authors jointly supervised this work.

                ¶ Memberships of CHARGE Consortium, DIAGRAM Consortium, GLGC Consortium, Global-BPGen Consortium, ICBP Consortium, MAGIC Consortium are provided in S2 Text.

                Article
                PGENETICS-D-14-03117
                10.1371/journal.pgen.1005378
                4591371
                26426971
                71d90d1c-a75d-4986-852f-e2515f92718b

                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
                : 19 November 2014
                : 22 June 2015
                Page count
                Figures: 4, Tables: 3, Pages: 42
                Funding
                Funding for this study was provided by the Aarne Koskelo Foundation; the Aase and Ejner Danielsens Foundation; the Academy of Finland (40758, 41071, 77299, 102318, 104781, 117787, 117844, 118590, 120315, 121584, 123885, 124243, 124282, 126925, 129269, 129293, 129378, 130326, 134309, 134791, 136895, 139635, 211497, 263836, 263924, 1114194, 24300796); the Agency for Health Care Policy Research (HS06516); the Agency for Science, Technology and Research of Singapore (A*STAR); the Ahokas Foundation; the ALF/LUA research grant in Gothenburg; the ALK-Abello´ A/S (Hørsholm, Denmark), Timber Merchant Vilhelm Bangs Foundation, MEKOS Laboratories Denmark; the Althingi (the Icelandic Parliament); the American Heart Association (AHA; 13POST16500011); the ANR ("Agence Nationale de la 359 Recherche"); the Ark (NHMRC Enabling Facility); the Arthritis Research UK (19542, 18030); the AstraZeneca; the Augustinus Foundation; the Australian National Health and Medical Research Council (NHMRC; 241944, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 496688, 552485, 613672, 613601 and 1011506); the Australian Research Council (ARC; DP0770096 and DP1093502); the Becket Foundation; the bi-national BMBF/ANR funded project CARDomics (01KU0908A); the Biobanking and Biomolecular Resources Research Infrastructure (BBMRINL; 184.021.007, CP 32); the Biocentrum Helsinki; the Boehringer Ingelheim Foundation; the British Heart Foundation (RG/10/12/28456, SP/04/002); the Canadian Institutes for Health Reseaerch (FRCN-CCT-83028); the Cancer Research UK (C490/A10124, C490/A10119); the Center for Medical Systems Biology (CMSB; NWO Genomics); the Centers for Disease Control and Prevention and Association of Schools of Public Health (1734, S043, S3486); the Centre of Excellence Baden-Württemberg Metabolic Disorders; the Chief Scientist Office of the Scottish Government; the Clinical Research Facility at Guys & St Thomas NHS Foundation Trust; the Contrat de Projets État-Région (CPER); the Croatian Science Council (Grant no. 8875); the CVON (GENIUS); the Danish Agency for Science, Technology and Innovation; the Danish Centre for Health Technology Assessment, Novo Nordisk Inc.; the Danish Council for Independent Research (DFF 1333-00124); the Danish Diabetes Association; Danish Heart Foundation; the Danish Medical Research Council; the Danish Ministry of Internal Affairs and Health; the Danish National Research Foundation; the Danish Pharmaceutical Association; Danish Pharmacists Fund; the Danish Research Council; the Deutsche Forschungsgemeinschaft; the Diabetes Hilfs- und Forschungsfonds Deutschland (DHFD); the Dr. Robert Pfleger-Stiftung; the Dresden University of Technology Funding Grant, Med Drive; the Dutch Brain Foundation; the Dutch Diabetes Research Foundation; the Dutch Economic Structure Enhancing Fund (FES); the Dutch Kidney Foundation; the Dutch Ministry for Health, Welfare and Sports; the Dutch Ministry of Economic Affairs; the Dutch Ministry of Education, Culture and Science; the Egmont Foundation; the Else Kröner-Fresenius Stiftung (2012_A147, P48/08//A11/08); the Emil Aaltonen Foundation; the Erasmus Medical Center and Erasmus University, Rotterdam; the Estonian Ministry of Science and Education (SF0180142s08); the European Commission (223004, 2004310, DGXII, FP6-EUROSPAN, FP6-EXGENESIS, FP6-LSHG-CT- 2006-018947, FP6-LSHG-CT- 2006-01947, FP6-LSHM-CT-2004-503485, FP6-LSHM-CT- 2006-037593, FP6-LSHM-CT-2007-037273, FP7-201379, FP7-201668, FP7-279143, FP7-305739, FP7-313010, FP7-ENGAGE-HEALTH-F4-2007-201413, FP7-EurHEALTHAgeing-277849, FP7-HEALTH-F4-2007-201550, HEALTH-2011.2.4.2-2-EU-MASCARA, HEALTH-F2-2008-201865-GEFOS, HEALTH-F7-305507 HOMAGE, LSHM-CT-2006-037593, QLG1-CT- 2001-01252, QLG1-CT-2002-00896, QLG2-CT-2002-01254); the European Regional Development Fund (ERDF) and the Wissenschaftsoffensive TMO; the European Regional Development Fund to the Centre of Excellence in Genomics (EXCEGEN; 3.2.0304.11-0312); the European Research Council (ERC; 2011-StG-280559-SEPI, 2011-294713-EPLORE, 230374); the European Science Foundation (ESF; EU/QLRT-2001-01254); the EuroSTRESS project FP-006; the Finlands Slottery Machine Association; the Finnish Centre for Pensions (ETK); the Finnish Cultural Foundation; the Finnish Diabetes Association; the Finnish Diabetes Research Foundation; the Finnish Foundation for Cardiovascular Research; the Finnish Foundation for Pediatric Research; the Finnish Funding Agency for Technology and Innovation (40058/07); the Finnish Medical Society; the Finnish Ministry of Education and Culture (627;2004–2011); the Finnish Ministry of Health and Social Affairs (5254); the Finnish National Public Health Institute (current National Institute for Health and Welfare); the Finnish Special Governmental Subsidy for Health Sciences; the Finska Läkaresällskapet, Signe and Ane Gyllenberg Foundation; the Flemish League against Cancer, ITEA2 (project Care4Me); the Folkhälsan Research Foundation; the Fonds voor Wetenschappelijk Onderzoek (FWO) Vlaanderen; the Foundation for Life and Health in Finland; the Foundation for Strategic Research (SSF) and the Stockholm County Council (560283); the G. Ph. Verhagen Foundation; the Gene-diet Interactions in Obesity' project (GENDINOB); the Genetic Association Information Network (GAIN); the GENEVA Coordinating Center (U01 HG 004446); the GenomEUtwin (EU/QLRT- 2001-01254; QLG2-CT-2002-01254); the German Bundesministerium fuer Forschung und Technology (01 AK 803 A-H, 01 IG 07015 G); the German Diabetes Association; the German Ministry of Cultural Affairs; the German Federal Ministry of Education and Research (BMBF; 03IS2061A, 03ZIK012, 01ZZ9603, 01ZZ0103, 01ZZ0403); the German National Genome Research Network (NGFN-2 and NGFN-plus); the German Research Council (SFB- 1052 "Obesity mechanisms"); the Great Wine Estates of the Margaret River region of Western Australia; the Greek General Secretary of Research and Technology research grant (PENED 2003); the Gyllenberg Foundation; the Health Care Centers in Vasa, Närpes and Korsholm; the Health Fund of the Danish Health Insurance Societies; the Helmholtz Zentrum München - German Research Center for Environmental Health; the Helsinki University Central Hospital special government funds (EVO #TYH7215, #TKK2012005, #TYH2012209); the Hjartavernd (the Icelandic Heart Association); the Ib Henriksen Foundation; the Illinois Department of Public Health, and the Translational Genomics Research Institute; the INTERREG IV Oberrhein Program (Project A28); the Interuniversity Cardiology Institute of the Netherlands (ICIN; 09.001); the Italian Ministry of Health "targeted project" (ICS110.1/RF97.71); the Italian National Centre of Research InterOmics PB05_SP3; the John D and Catherine T MacArthur Foundation Research Networks on Successful Midlife Development and Socio-economic Status and Health; the Johns Hopkins University Center for Inherited Disease Research (CIDR); the Joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg- West Pomerania; the Juho Vainio Foundation; the Juselius Foundation (Helsinki, Finland); the Juvenile Diabetes Research Foundation International (JDRF); the KfH Stiftung Präventivmedizin e.V.; the Knut and Alice Wallenberg Foundation; the Kuopio University Hospital; the Leenaards Foundation; the Leiden University Medical Center; the Liv och Hälsa; the Local Government Pensions Institution (KEVA); the Lokaal Gezondheids Overleg (LOGO) Leuven and Hageland; the Ludwig-Maximilians-Universität, as part of LMUinnovativ; the Lundberg Foundation; the March of Dimes Birth Defects Foundation; the Medical Research Council (G0601966; G0700931; G0000934; G0500539; G0600705; G1002319; G0701863; PrevMetSyn/SALVE; MC_U106179471; MC_UU_12019/1); the MRC centre for Causal Analyses in Translational Epidemiology (MRC CAiTE); the MRC Centre for Obesity and Related Metabolic Diseases; the MRC Human Genetics Unit; the Medical Research Council of Canada; the Mid-Atlantic Nutrition and Obesity Research Center (P30 DK072488); the Ministry of the Flemish Community, Brussels, Belgium (G.0881.13 and G.0880.13); the MIUR - CNR Italian Flagship Project; the Montreal Heart Institute Foundation; the Munich Center of Health Sciences (MC Health); the Municipal Health Care Center and Hospital in Jakobstad; the Närpes Health Care Foundation; the National Alliance for Research on Schizophrenia and Depression (NARSAD); the National Cancer Institute (CA047988); the National Center for Advancing Translational Sciences (UL1TR000124); the National Center for Research Resources (U54RR020278); the National Heart, Lung and Blood Institute (NHLBI, 1RL1MH083268-01, 5R01HL087679-02, HHSN268200800007C, HHSN268201200036C, HL043851, HL080467, HL087647, HL36310, HL45670, N01HC25195, N01HC55015, N01HC55016, N01HC55018, N01HC55019, N01HC55020, N01HC55021, N01HC55022, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, N02HL64278, R01HL086694, R01HL087641, R01HL087652, R01HL087676, R01HL59367, R01HL103612, R01HL105756, R01HL120393, U01HL080295); the National Human Genome Research Institute (NHGRI, U01HG004402); the National Institute for Health and Welfare (THL); the National Institute for Health Research (NIHR, RP-PG-0407-10371); the National Institute of Allergy and Infectious Diseases (NIAID); the National Institute of Child Health and Human Development (NICHD); the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK-DRC, 1R01DK8925601, DK063491, R01DK089256, P30 DK072488); the National Institute of Food and Agriculture (2007-35205-17883); the National Institute of Neurological Disorders and Stroke (NINDS); the National Institute on Aging (NIA; 263-MA-410953, 263-MD-821336, 263-MD-9164, AG023629, AG13196, NO1AG12109, P30AG10161, R01AG15819, R01AG17917, R01AG023629, R01AG30146); the National Institute of Arthritis and Musculoskeletal and Skin Diseases (5-P60-AR30701, 5-P60-AR49465-03); the National Institutes of Health (NIH; 1R01DK8925601, 1RC2MH089951, 1RC2MH089995, 1Z01HG000024, 2T32 HL 007055-36, 5R01DK075681, 5R01MH63706:02, AA014041, AA07535, AA10248, AA13320, AA13321, AA13326, AG028555, AG08724, AG04563, AG10175, AG08861, DA12854, DK046200, DK091718, F32AR059469, HG002651, HHSN268200625226C, HHSN268200782096C, HL084729, MH081802, N01-AG12100, N01HG65403, R01AG011101, R01AG030146, R01D0042157-01A, R01DK062370, R01DK072193, R01DK093757, R01DK075787, R01DK075787, R01HL71981, R01MH59565, R01MH59566, R01MH59571, R01MH59586, R01MH59587, R01MH59588, R01MH60870, R01MH60879, R01MH61675, R01MH67257, R01MH81800, R01NS45012, U01066134, U01CA098233, U01DK062418, U01GM074518, U01HG004423, U01HG004436, U01HG004438, U01HL072515-06, U01HL105198, U01HL84756, U01MH79469, U01MH79470, U01NS069208-01, UL1RR025005); the NIHR Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust; the NIHR Cambridge Biomedical research Centre; the Netherlands Heart Foundation (2001 D 032); the Netherlands Organisation for Scientific Research (NWO; Geestkracht program grant 10-000-1002; 050-060-810; 100-001-004; 175.010.2003.005; 175.010.2005.011; 175.010.2007.006; 261-98-710; 40-0056-98-9032; 400-05-717; 452-04-314; 452-06-004; 480-01-006; 480-04-004; 480-05-003; 480-07-001; 481-08-013; 60-60600-97-118; 904-61-090; 904-61-193; 911-03-012; 985-10-002; Addiction-31160008; GB-MW 940-38-011; SPI 56-464-14192); the Netherlands Organization for the Health Research and Development (ZonMw; 91111025); the Nordic Center of Excellence in Disease Genetics; the Nordic Centre of Excellence on Systems biology in controlled dietary interventions and cohort studies, SYSDIET (070014); the Northern Netherlands Collaboration of Provinces (SNN); the Novo Nordisk Foundation; the Office of Research and Development, Medical Research Service, and the Baltimore Geriatrics Research, Education, and Clinical Center of the Department of Veterans Affairs; the Ollqvist Foundation; the Paavo Nurmi Foundation; the Påhlssons Foundation; the Päivikki and Sakari Sohlberg Foundation; the Perklén Foundation; the Republic of Croatia Ministry of Science, Education and Sports research (108-1080315-0302); the Research Centre for Prevention and Health, the Capital Region of Denmark; the Research Foundation of Copenhagen County; the Research Institute for Diseases in the Elderly (014-93-015; RIDE2); the Reynold's Foundation; the Rotterdam Oncologic Thoracic Study Group, Erasmus Trust Fund, Foundation against Cancer; the Royal Swedish Academy of Science; the Russian Foundation for Basic Research (NWO-RFBR 047.017.043); the Rutgers University Cell and DNA Repository cooperative agreement (NIMH U24 MH068457-06); the Samfundet Folkhälsan; the Sigrid Juselius Foundation; the Social Insurance Institution of Finland, Kuopio, Tampere and Turku University Hospital Medical Funds (9M048, 9N035); the Social Ministry of the Federal State of Mecklenburg-West Pomerania; the Société Francophone du 358 Diabète (SFD); the South Tyrolean Sparkasse Foundation; the Stichting Nationale Computerfaciliteiten (National Computing Facilities Foundation, NCF); the Strategic Cardiovascular Programme of Karolinska Institutet and the Stockholm County Council (560183); the Susan G. Komen Breast Cancer Foundation; the Swedish Cancer Society; the Swedish Cultural Foundation in Finland; the Swedish Diabetes Association; the Swedish Diabetes Foundation (grant no. 2013-024); the Swedish Foundation for Strategic Research (SSF; ICA08-0047); the Swedish Heart-Lung Foundation (20120197); the Swedish Medical Research Council (K2007-66X-20270-01-3, 2012-1397); the Swedish Ministry for Higher Education; the Swedish Research Council (8691, M-2005-1112, 2009-2298); the Swedish Society for Medical Research; the Swiss National Science Foundation (31003A-143914, 3200B0105993, 3200B0-118308, 33CSCO-122661, 33CS30-139468, 33CS30-148401); SystemsX.ch (51RTP0_151019); the Tampere Tuberculosis Foundation; the TEKES (70103/06, 40058/07); the The Paul Michael Donovan Charitable Foundation; the Torsten and Ragnar Söderberg Foundation; the Umeå Medical Research Foundation; the United Kingdom NIHR Cambridge Biomedical Research Centre; the Universities and Research of the Autonomous Province of Bolzano, South Tyrol; the University Hospital of Regensburg (ReForM A, ReForM C); the University Hospital Oulu, Biocenter, University of Oulu, Finland (75617); the University Medical Center Groningen; the University of Groningen; the University of Maryland General Clinical Research Center (M01RR16500, AG000219); the University of Tartu (SP1GVARENG); the University of Tromsø, Norwegian Research Council (185764); the Västerbottens Intervention Programme; the Velux Foundation; the VU University Institute for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam (NCA); the Wellcome Trust (064890, 068545/Z/02, 076113/B/04/Z, 077016/Z/05/Z, 079895, 084723/Z/08/Z, 086596/Z/08/Z, 088869/B/09/Z, 089062, 090532, 098017, 098051, 098381); the Western Australian DNA Bank (NHMRC Enabling Facility); the Yrjö Jahnsson Foundation (56358); and the Zorg Onderzoek Nederland-Medische Wetenschappen, KWF Kankerbestrijding, Stichting Centraal Fonds Reserves van voormalig Vrijwillige Ziekenfondsverzekeringen. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. More details of acknowledgements can be found in S2 Text.
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                The stratified genome-wide association meta-analysis results for BMI and waist-hip ratio are available from the GIANT Consortium website www.broadinstitute.org/collaboration/giant

                Genetics
                Genetics

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