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      Genetic studies of body mass index yield new insights for obesity biology.

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          Abstract

          Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

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          Author and article information

          Journal
          Nature
          Nature
          Springer Nature
          1476-4687
          0028-0836
          Feb 12 2015
          : 518
          : 7538
          Affiliations
          [1 ] Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA.
          [2 ] Department of Internal Medicine, Division of Gastroenterology, and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan 48109, USA.
          [3 ] Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
          [4 ] Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
          [5 ] 1] Divisions of Endocrinology and Genetics and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts 02115, USA. [2] Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA. [3] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA. [4] Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby 2800, Denmark.
          [6 ] MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
          [7 ] 1] Divisions of Endocrinology and Genetics and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts 02115, USA. [2] Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA.
          [8 ] Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
          [9 ] 1] Queensland Brain Institute, The University of Queensland, Brisbane 4072, Australia. [2] The University of Queensland Diamantina Institute, The Translation Research Institute, Brisbane 4012, Australia.
          [10 ] 1] Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA. [2] Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
          [11 ] 1] Divisions of Endocrinology and Genetics and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts 02115, USA. [2] Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA. [3] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA. [4] Estonian Genome Center, University of Tartu, Tartu 51010, Estonia.
          [12 ] 1] Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden. [2] Science for Life Laboratory, Uppsala University, Uppsala 75185, Sweden. [3] Department of Medical Sciences, Molecular Epidemiology, Uppsala University, Uppsala 75185, Sweden.
          [13 ] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
          [14 ] 1] Science for Life Laboratory, Uppsala University, Uppsala 75185, Sweden. [2] Department of Medical Sciences, Molecular Epidemiology, Uppsala University, Uppsala 75185, Sweden.
          [15 ] 1] Institute of Social and Preventive Medicine (IUMSP), Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne 1010, Switzerland. [2] Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland. [3] Department of Medical Genetics, University of Lausanne, Lausanne 1005, Switzerland.
          [16 ] 1] Estonian Genome Center, University of Tartu, Tartu 51010, Estonia. [2] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
          [17 ] 1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. [2] Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
          [18 ] Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University of Regensburg, D-93053 Regensburg, Germany.
          [19 ] Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter EX1 2LU, UK.
          [20 ] Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
          [21 ] Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, Michigan 48104, USA.
          [22 ] Department of Epidemiology, University of Michigan, Ann Arbor, Michigan 48109, USA.
          [23 ] Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.
          [24 ] Department of Genetics, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands.
          [25 ] 1] Science for Life Laboratory, Uppsala University, Uppsala 75185, Sweden. [2] Department of Medical Sciences, Molecular Epidemiology, Uppsala University, Uppsala 75185, Sweden. [3] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
          [26 ] Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan 48109, USA.
          [27 ] HudsonAlpha Institute for Biotechnology, Huntsville, Alabama 35806, USA.
          [28 ] Genetic Epidemiology Unit, Department of Epidemiology, Erasmus MC University Medical Center, 3015 GE Rotterdam, The Netherlands.
          [29 ] Telethon Institute for Child Health Research, Centre for Child Health Research, The University of Western Australia, Perth, Western Australia 6008, Australia.
          [30 ] 1] Netherlands Consortium for Healthy Aging (NCHA), Leiden University Medical Center, Leiden 2300 RC, The Netherlands. [2] Department of Molecular Epidemiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
          [31 ] Centre for Population Health Sciences, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK.
          [32 ] 1] Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA. [2] Kidney Epidemiology and Cost Center, University of Michigan, Ann Arbor, Michigan 48109, USA.
          [33 ] 1] Department of Statistics &Biostatistics, Rutgers University, Piscataway, New Jersey 08854, USA. [2] Department of Genetics, Rutgers University, Piscataway, New Jersey 08854, USA.
          [34 ] 1] Genetic Epidemiology Unit, Department of Epidemiology, Erasmus MC University Medical Center, 3015 GE Rotterdam, The Netherlands. [2] Department of Human Genetics, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands.
          [35 ] 1] Ealing Hospital NHS Trust, Middlesex UB1 3HW, UK. [2] Department of Gastroenterology and Hepatology, Imperial College London, London W2 1PG, UK. [3] Institute of infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China.
          [36 ] 1] Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. [2] Cardiology, Department of Specialties of Internal Medicine, Geneva University Hospital, Geneva 1211, Switzerland.
          [37 ] Department of Epidemiology Research, Statens Serum Institut, Copenhagen DK-2300, Denmark.
          [38 ] Department of Genetics, Washington University School of Medicine, St Louis, Missouri 63110, USA.
          [39 ] Estonian Genome Center, University of Tartu, Tartu 51010, Estonia.
          [40 ] 1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. [2] Division of Cardiovacular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK.
          [41 ] Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
          [42 ] William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
          [43 ] 1] Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, D-68187 Mannheim, Germany. [2] Department of Internal Medicine II, Ulm University Medical Centre, D-89081 Ulm, Germany.
          [44 ] National Institute for Health and Welfare, FI-00271 Helsinki, Finland.
          [45 ] Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii 96813, USA.
          [46 ] The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
          [47 ] Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK.
          [48 ] Department of Cardiology, University Medical Center Groningen, University of Groningen, 9700RB Groningen, The Netherlands.
          [49 ] 1] Netherlands Consortium for Healthy Aging (NCHA), 3015GE Rotterdam, The Netherlands. [2] Department of Epidemiology, Erasmus MC University Medical Center, 3015GE Rotterdam, The Netherlands. [3] Department of Internal Medicine, Erasmus MC University Medical Center, 3015GE Rotterdam, The Netherlands.
          [50 ] QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
          [51 ] Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA.
          [52 ] Institute for Medical Informatics, Biometry and Epidemiology (IMIBE), University Hospital Essen, 45147 Essen, Germany.
          [53 ] 1] Netherlands Consortium for Healthy Aging (NCHA), 3015GE Rotterdam, The Netherlands. [2] Department of Internal Medicine, Erasmus MC University Medical Center, 3015GE Rotterdam, The Netherlands.
          [54 ] 1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. [2] Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LJ, UK. [3] Department of Genomics of Common Disease, School of Public Health, Imperial College London, Hammersmith Hospital, London W12 0NN, UK.
          [55 ] 1] Department of Clinical Sciences, Genetic &Molecular Epidemiology Unit, Lund University Diabetes Center, Skåne University Hosptial, Malmö 205 02, Sweden. [2] Department of Public Health and Clinical Medicine, Unit of Medicine, Umeå University, Umeå 901 87, Sweden. [3] Department of Odontology, Umeå University, Umeå 901 85, Sweden.
          [56 ] University of Eastern Finland, FI-70210 Kuopio, Finland.
          [57 ] Atherosclerosis Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm 17176, Sweden.
          [58 ] Division of Biostatistics, Washington University School of Medicine, St Louis, Missouri 63110, USA.
          [59 ] Translational Gerontology Branch, National Institute on Aging, Baltimore, Maryland 21225, USA.
          [60 ] Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, D-17475 Greifswald, Germany.
          [61 ] 1] Department of Cardiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands. [2] Department of Gerontology and Geriatrics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
          [62 ] Experimental Cardiology Laboratory, Division Heart and Lungs, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
          [63 ] Department of Medical Genetics, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
          [64 ] Department of Endocrinology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The Netherlands.
          [65 ] 1] Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. [2] Core Genotyping Facility, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland 21702, USA.
          [66 ] 1] CNRS UMR 8199, F-59019 Lille, France. [2] European Genomic Institute for Diabetes, F-59000 Lille, France. [3] Université de Lille 2, F-59000 Lille, France.
          [67 ] 1] Ealing Hospital NHS Trust, Middlesex UB1 3HW, UK. [2] Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK.
          [68 ] 1] Genetic Epidemiology Unit, Department of Epidemiology, Erasmus MC University Medical Center, 3015 GE Rotterdam, The Netherlands. [2] Center for Medical Sytems Biology, 2300 RC Leiden, The Netherlands.
          [69 ] Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, D-85764 Neuherberg, Germany.
          [70 ] 1] Science for Life Laboratory, Uppsala University, Uppsala 75185, Sweden. [2] Department of Medical Sciences, Molecular Epidemiology, Uppsala University, Uppsala 75185, Sweden. [3] School of Health and Social Studies, Dalarna University, SE-791 88 Falun, Sweden.
          [71 ] PathWest Laboratory Medicine of Western Australia, Nedlands, Western Australia 6009, Australia.
          [72 ] 1] Department of Haematology, University of Cambridge, Cambridge CB2 0PT, UK. [2] NHS Blood and Transplant, Cambridge CB2 0PT, UK.
          [73 ] Geriatric Unit, Azienda Sanitaria Firenze (ASF), 50125 Florence, Italy.
          [74 ] Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LJ, UK.
          [75 ] USC-Office of Population Studies Foundation, Inc., University of San Carlos, Cebu City 6000, Philippines.
          [76 ] 1] Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas 78227, USA. [2] Genomics Research Centre, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland 4001, Australia.
          [77 ] Department of Medical Sciences, Endocrinology, Diabetes and Metabolism, Uppsala University, Uppsala 75185, Sweden.
          [78 ] Division of Endocrinology, Diabetes and Metabolism, Ulm University Medical Centre, D-89081 Ulm, Germany.
          [79 ] 1] Integrated Research and Treatment Center (IFB) Adiposity Diseases, University of Leipzig, D-04103 Leipzig, Germany. [2] Department of Medicine, University of Leipzig, D-04103 Leipzig, Germany.
          [80 ] 1] Netherlands Consortium for Healthy Aging (NCHA), Leiden University Medical Center, Leiden 2300 RC, The Netherlands. [2] Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
          [81 ] Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland 20892, USA.
          [82 ] Integrated Research and Treatment Center (IFB) Adiposity Diseases, University of Leipzig, D-04103 Leipzig, Germany.
          [83 ] LifeLines Cohort Study, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands.
          [84 ] Department of Biology, Norwegian University of Science and Technology, 7491 Trondheim, Norway.
          [85 ] 1] Department of Pediatrics, University of California Los Angeles, Torrance, California 90502, USA. [2] Transgenomics Institute, Los Angeles Biomedical Research Institute, Torrance, California 90502, USA.
          [86 ] Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, UK.
          [87 ] Department of Gerontology and Geriatrics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
          [88 ] Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, D-68187 Mannheim, Germany.
          [89 ] Department of Dietetics-Nutrition, Harokopio University, 17671 Athens, Greece.
          [90 ] Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
          [91 ] 1] National Institute for Health and Welfare, FI-00271 Helsinki, Finland. [2] Institute for Molecular Medicine, University of Helsinki, FI-00014 Helsinki, Finland.
          [92 ] 1] Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA. [2] Department of Internal Medicine, Erasmus MC University Medical Center, 3015GE Rotterdam, The Netherlands. [3] Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
          [93 ] Laboratory of Epidemiology and Population Sciences, National Institute on Aging, NIH, Bethesda, Maryland 20892, USA.
          [94 ] Department of Public Health and Caring Sciences, Geriatrics, Uppsala University, Uppsala 75185, Sweden.
          [95 ] Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden, Stockholm 17177, Sweden.
          [96 ] Kaiser Permanente, Division of Research, Oakland, California 94612, USA.
          [97 ] Service of Therapeutic Education for Diabetes, Obesity and Chronic Diseases, Geneva University Hospital, Geneva CH-1211, Switzerland.
          [98 ] 1] Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester LE3 9QP, UK. [2] National Institute for Health Research (NIHR) Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester LE3 9QP, UK.
          [99 ] 1] Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University of Regensburg, D-93053 Regensburg, Germany. [2] Department of Nephrology, University Hospital Regensburg, D-93053 Regensburg, Germany.
          [100 ] 1] Department of Psychiatry and Psychotherapy, University Medicine Greifswald, HELIOS-Hospital Stralsund, D-17475 Greifswald, Germany. [2] German Center for Neurodegenerative Diseases (DZNE), Rostock, Greifswald, D-17475 Greifswald, Germany.
          [101 ] 1] Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, D-85764 Neuherberg, Germany. [2] Research Unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, D-85764 Neuherberg, Germany. [3] German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany.
          [102 ] Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, D-01307 Dresden, Germany.
          [103 ] Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden.
          [104 ] Institut inter Régional pour la Santé, Synergies, F-37520 La Riche, France.
          [105 ] Department of Public Health and Clinical Medicine, Unit of Nutritional Research, Umeå University, Umeå 90187, Sweden.
          [106 ] Department of Psychiatry, University of Groningen, University Medical Center Groningen, 9700RB Groningen, The Netherlands.
          [107 ] Kuopio Research Institute of Exercise Medicine, 70100 Kuopio, Finland.
          [108 ] MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.
          [109 ] 1] National Heart, Lung, and Blood Institute, the Framingham Heart Study, Framingham, Massachusetts 01702, USA. [2] Department of Neurology, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
          [110 ] 1] Netherlands Consortium for Healthy Aging (NCHA), Leiden University Medical Center, Leiden 2300 RC, The Netherlands. [2] Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands. [3] Faculty of Psychology and Education, VU University Amsterdam, 1081BT Amsterdam, The Netherlands.
          [111 ] 1] Deutsches Forschungszentrum für Herz-Kreislauferkrankungen (DZHK) (German Research Centre for Cardiovascular Research), Munich Heart Alliance, D-80636 Munich, Germany. [2] Deutsches Herzzentrum München, Technische Universität München, D-80636 Munich, Germany.
          [112 ] Department of Public Health and General Practice, Norwegian University of Science and Technology, Trondheim 7489, Norway.
          [113 ] Biological Psychology, VU University Amsterdam, 1081BT Amsterdam, The Netherlands.
          [114 ] 1] Department of Pulmonary Physiology and Sleep Medicine, Nedlands, Western Australia 6009, Australia. [2] School of Medicine and Pharmacology, University of Western Australia, Crawley 6009, Australia.
          [115 ] Uppsala University, Department of Immunology, Genetics, Pathology, SciLifeLab, Rudbeck Laboratory, SE-751 85 Uppsala, Sweden.
          [116 ] Department of Internal Medicine II, Ulm University Medical Centre, D-89081 Ulm, Germany.
          [117 ] Hjelt Institute Department of Public Health, University of Helsinki, FI-00014 Helsinki, Finland.
          [118 ] Department of Internal Medicine I, Ulm University Medical Centre, D-89081 Ulm, Germany.
          [119 ] Finnish Institute of Occupational Health, FI-90100 Oulu, Finland.
          [120 ] Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, 6020 Innsbruck, Austria.
          [121 ] Institute of Human Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, D-85764 Neuherberg, Germany.
          [122 ] Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala 75185, Sweden.
          [123 ] Montreal Heart Institute, Montreal, Quebec H1T 1C8, Canada.
          [124 ] Institute for Community Medicine, University Medicine Greifswald, D-17475 Greifswald, Germany.
          [125 ] 1] The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA. [2] The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
          [126 ] Cardiology, Department of Specialties of Internal Medicine, Geneva University Hospital, Geneva 1211, Switzerland.
          [127 ] School of Social and Community Medicine, University of Bristol, Bristol BS8 2BN, UK.
          [128 ] 1] Estonian Genome Center, University of Tartu, Tartu 51010, Estonia. [2] Institute of Molecular and Cell Biology, University of Tartu, Tartu 51010, Estonia.
          [129 ] 1] Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK. [2] Farr Institute of Health Informatics Research, University College London, London NW1 2DA, UK.
          [130 ] 1] Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA. [2] The Center for Observational Research, Amgen, Inc., Thousand Oaks, California 91320, USA.
          [131 ] Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche, Cagliari, Sardinia 09042, Italy.
          [132 ] Center for Evidence-based Healthcare, University Hospital Carl Gustav Carus, Technische Universität Dresden, D-01307 Dresden, Germany.
          [133 ] 1] Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, D-85764 Neuherberg, Germany. [2] Deutsches Forschungszentrum für Herz-Kreislauferkrankungen (DZHK) (German Research Centre for Cardiovascular Research), Munich Heart Alliance, D-80636 Munich, Germany. [3] Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universität, D-81377 Munich, Germany. [4] Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, D-81377 Munich, Germany.
          [134 ] Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Nedlands, Western Australia 6009, Australia.
          [135 ] Laboratory of Genetics, National Institute on Aging, Baltimore, Maryland 21224, USA.
          [136 ] 1] Department of Genomics, Life &Brain Center, University of Bonn, 53127 Bonn, Germany. [2] Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany.
          [137 ] Department of Epidemiology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands.
          [138 ] 1] Department of Epidemiology and Biostatistics, Institute for Research in Extramural Medicine, Institute for Health and Care Research, VU University Medical Center, 1081BT Amsterdam, The Netherlands. [2] Department of Internal Medicine, Division of Endocrinology and Metabolism, Medical University of Graz, 8036 Graz, Austria.
          [139 ] 1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. [2] Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK. [3] Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LJ, UK.
          [140 ] Department of Clinical Sciences, Genetic &Molecular Epidemiology Unit, Lund University Diabetes Center, Skåne University Hosptial, Malmö 205 02, Sweden.
          [141 ] Institute of Physiology, University Medicine Greifswald, D-17495 Karlsburg, Germany.
          [142 ] 1] Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. [2] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
          [143 ] 1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. [2] Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LJ, UK.
          [144 ] Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA.
          [145 ] Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz 8036, Austria.
          [146 ] Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, USA.
          [147 ] National Cancer Institute, Bethesda, Maryland 20892, USA.
          [148 ] 1] Icelandic Heart Association, Kopavogur 201, Iceland. [2] University of Iceland, Reykjavik 101, Iceland.
          [149 ] 1] Department of Genetics, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands. [2] Department of Epidemiology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands.
          [150 ] Molecular &Cellular Therapeutics, Royal College of Surgeons in Ireland, 123 St Stephen's Green, Dublin 2, Ireland.
          [151 ] deCODE Genetics, Amgen Inc., Reykjavik 101, Iceland.
          [152 ] 1] Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK. [2] William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
          [153 ] 1] Science for Life Laboratory, Uppsala University, Uppsala 75185, Sweden. [2] Department of Medical Sciences, Molecular Medicine, Uppsala University, Uppsala 75144, Sweden.
          [154 ] 1] Ealing Hospital NHS Trust, Middlesex UB1 3HW, UK. [2] National Heart and Lung Institute, Imperial College London, London SW3 6LY, UK.
          [155 ] Department of Public Health Sciences, Stritch School of Medicine, Loyola University of Chicago, Maywood, Illinois 61053, USA.
          [156 ] 1] German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany. [2] Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany, D-85764 Neuherberg, Germany.
          [157 ] Department of Oncology, University of Cambridge, Cambridge CB2 0QQ, UK.
          [158 ] Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg 413 45, Sweden.
          [159 ] Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC University Medical Centre, 3000 CB Rotterdam, The Netherlands.
          [160 ] 1] Department for Health Evidence, Radboud University Medical Centre, 6500 HB Nijmegen, The Netherlands. [2] Department of Genetics, Radboud University Medical Centre, 6500 HB Nijmegen, The Netherlands.
          [161 ] Department of Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
          [162 ] Genetics, GlaxoSmithKline, King of Prussia, Pennsylvania 19406, USA.
          [163 ] 1] German Center for Cardiovascular Research, partner site Hamburg/Lubeck/Kiel, 23562 Lubeck, Germany. [2] Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, D-23562 Lübeck, Germany.
          [164 ] Department of Community Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, 9037 Tromsø, Norway.
          [165 ] MRC Unit for Lifelong Health and Ageing at University College London, London WC1B 5JU, UK.
          [166 ] Diabetes Complications Research Centre, Conway Institute, School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland.
          [167 ] Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
          [168 ] Lady Davis Institute, Departments of Human Genetics, Epidemiology and Biostatistics, McGill University, Montréal, Québec H3T1E2, Canada.
          [169 ] Cardiothoracic Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm 17176, Sweden.
          [170 ] Department of Medicine, Columbia University College of Physicians and Surgeons, New York 10032, USA.
          [171 ] 1] Biosciences Research Division, Department of Primary Industries, Victoria 3083, Australia. [2] Department of Food and Agricultural Systems, University of Melbourne, Victoria 3010, Australia.
          [172 ] 1] Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA. [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
          [173 ] 1] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA. [2] State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China.
          [174 ] 1] Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LJ, UK. [2] NIHR Oxford Biomedical Research Centre, OUH Trust, Oxford OX3 7LE, UK.
          [175 ] 1] Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA. [2] Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
          [176 ] Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
          [177 ] Center for Genome Science, National Institute of Health, Chungcheongbuk-do, Chungbuk 363-951, Republic of Korea.
          [178 ] 1] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA. [2] Harvard School of Public Health, Department of Biostatistics, Harvard University, Boston, Massachusetts 2115, USA.
          [179 ] Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, New Haven, Connecticut 06520, USA.
          [180 ] 1] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA. [2] College of Information Science and Technology, Dalian Maritime University, Dalian, Liaoning 116026, China.
          [181 ] 1] Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA. [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA. [3] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
          [182 ] Nephrology Research, Centre for Public Health, Queen's University of Belfast, Belfast, County Down BT9 7AB, UK.
          [183 ] National Heart and Lung Institute, Imperial College London, London SW3 6LY, UK.
          [184 ] 1] National Heart, Lung, and Blood Institute, the Framingham Heart Study, Framingham, Massachusetts 01702, USA. [2] Section of General Internal Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
          [185 ] 1] Department of Statistics, University of Oxford, 1 South Parks Road, Oxford OX1 3TG, UK. [2] MRC Harwell, Harwell Science and Innovation Campus, Harwell OX11 0QG, UK.
          [186 ] 1] QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia. [2] Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland 4059, Australia.
          [187 ] 1] Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan. [2] Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 113-8510 Tokyo, Japan.
          [188 ] 1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. [2] Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter EX1 2LU, UK. [3] Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK.
          [189 ] Genome Institute of Singapore, Agency for Science, Technology and Research, 138672 Singapore.
          [190 ] 1] Divisions of Endocrinology and Genetics and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts 02115, USA. [2] Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA. [3] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
          [191 ] 1] Department of Biomedical Engineering and Computational Science, Aalto University School of Science, Helsinki FI-00076, Finland. [2] Department of Medicine, Division of Nephrology, Helsinki University Central Hospital, FI-00290 Helsinki, Finland. [3] Folkhälsan Institute of Genetics, Folkhälsan Research Center, FI-00290 Helsinki, Finland.
          [192 ] 1] Netherlands Consortium for Healthy Aging (NCHA), Leiden University Medical Center, Leiden 2300 RC, The Netherlands. [2] Department of Internal Medicine, Erasmus MC University Medical Center, 3015GE Rotterdam, The Netherlands.
          [193 ] Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
          [194 ] 1] Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 113-8510 Tokyo, Japan. [2] Laboratory for Cardiovascular Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan. [3] Division of Disease Diversity, Bioresource Research Center, Tokyo Medical and Dental University, 113-8510 Tokyo, Japan.
          [195 ] Queensland Brain Institute, The University of Queensland, Brisbane 4072, Australia.
          [196 ] Division of Epidemiology, Department of Medicine; Vanderbilt Epidemiology Center; and Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee 37075, USA.
          [197 ] 1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. [2] Nuffield Department of Obstetrics &Gynaecology, University of Oxford, Oxford OX3 7BN, UK.
          [198 ] Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri 63110, USA.
          [199 ] Department of Epidemiology and Public Health, EA3430, University of Strasbourg, Faculty of Medicine, Strasbourg, France.
          [200 ] Department of Internal Medicine, University Medical Center Groningen, University of Groningen, 9700RB Groningen, The Netherlands.
          [201 ] 1] PathWest Laboratory Medicine of Western Australia, Nedlands, Western Australia 6009, Australia. [2] Pathology and Laboratory Medicine, The University of Western Australia, Perth, Western Australia 6009, Australia.
          [202 ] Cedars-Sinai Diabetes and Obesity Research Institute, Los Angeles, California 90048, USA.
          [203 ] Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas 78227, USA.
          [204 ] 1] Institute of Social and Preventive Medicine (IUMSP), Centre Hospitalier Universitaire Vaudois and University of Lausanne, 1010 Lausanne, Switzerland. [2] Ministry of Health, Victoria, Republic of Seychelles.
          [205 ] University of Milano, Bicocca, 20126, Italy.
          [206 ] Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
          [207 ] 1] Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA. [2] Harvard Medical School, Boston, Massachusetts 02115, USA.
          [208 ] 1] Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, Tennessee 37203, USA. [2] Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee 37232, USA.
          [209 ] 1] National Heart, Lung, and Blood Institute, the Framingham Heart Study, Framingham, Massachusetts 01702, USA. [2] Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA.
          [210 ] 1] Department of Health Sciences, University of Milano, I 20142, Italy. [2] Fondazione Filarete, Milano I 20139, Italy.
          [211 ] Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
          [212 ] 1] Experimental Cardiology Laboratory, Division Heart and Lungs, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands. [2] Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
          [213 ] Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK.
          [214 ] Clinic of Cardiology, West-German Heart Centre, University Hospital Essen, 45147 Essen, Germany.
          [215 ] 1] National Institute for Health and Welfare, FI-00271 Helsinki, Finland. [2] Department of General Practice and Primary Health Care, University of Helsinki, FI-00290 Helsinki, Finland. [3] Unit of General Practice, Helsinki University Central Hospital, Helsinki 00290, Finland.
          [216 ] 1] Department of Internal Medicine B, University Medicine Greifswald, D-17475 Greifswald, Germany. [2] DZHK (Deutsches Zentrum für Herz-Kreislaufforschung - German Centre for Cardiovascular Research), partner site Greifswald, D-17475 Greifswald, Germany.
          [217 ] 1] Department of Internal Medicine, University of Pisa, 56100 Pisa, Italy. [2] National Research Council Institute of Clinical Physiology, University of Pisa, 56124 Pisa, Italy.
          [218 ] Department of Cardiology, Toulouse University School of Medicine, Rangueil Hospital, 31400 Toulouse, France.
          [219 ] Robertson Center for Biostatistics, University of Glasgow, Glasgow G12 8QQ, UK.
          [220 ] UWI Solutions for Developing Countries, The University of the West Indies, Mona, Kingston 7, Jamaica.
          [221 ] 1] Netherlands Consortium for Healthy Aging (NCHA), 3015GE Rotterdam, The Netherlands. [2] Department of Epidemiology, Erasmus MC University Medical Center, 3015GE Rotterdam, The Netherlands.
          [222 ] NorthShore University HealthSystem, Evanston, IL 60201, University of Chicago, Chicago, Illinois, USA.
          [223 ] Leeds MRC Medical Bioinformatics Centre, University of Leeds, Leeds LS2 9LU, UK.
          [224 ] Institute of Biomedical &Clinical Science, University of Exeter, Barrack Road, Exeter EX2 5DW, UK.
          [225 ] Center for Biomedicine, European Academy Bozen, Bolzano (EURAC), Bolzano 39100, Italy (affiliated institute of the University of Lübeck, D-23562 Lübeck, Germany).
          [226 ] Division of Genomic Medicine, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
          [227 ] Institute of Cardiovascular Science, University College London, London WC1E 6BT, UK.
          [228 ] Department of Vascular Medicine, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands.
          [229 ] Centre for Cardiovascular Genetics, Institute Cardiovascular Sciences, University College London, London WC1E 6JJ, UK.
          [230 ] Cardiovascular Genetics Division, Department of Internal Medicine, University of Utah, Salt Lake City, Utah 84108, USA.
          [231 ] 1] Sansom Institute for Health Research, University of South Australia, Adelaide 5000, South Australia, Australia. [2] School of Population Health, University of South Australia, Adelaide 5000, South Australia, Australia. [3] South Australian Health and Medical Research Institute, Adelaide, South Australia 5000, Australia. [4] Population, Policy, and Practice, University College London Institute of Child Health, London WC1N 1EH, UK.
          [232 ] 1] Research Unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, D-85764 Neuherberg, Germany. [2] Hannover Unified Biobank, Hannover Medical School, Hannover, D-30625 Hannover, Germany.
          [233 ] 1] Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK. [2] National Institute for Health and Welfare, FI-90101 Oulu, Finland. [3] MRC Health Protection Agency (HPA) Centre for Environment and Health, School of Public Health, Imperial College London, London W2 1PG, UK. [4] Unit of Primary Care, Oulu University Hospital, FI-90220 Oulu, Finland. [5] Institute of Health Sciences, University of Oulu, FI-90014 Oulu, Finland. [6] Institute of Health Sciences, University of Oulu, FI-90014 Oulu, Finland.
          [234 ] 1] Department of Cardiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands. [2] Durrer Center for Cardiogenetic Research, Interuniversity Cardiology Institute Netherlands (ICIN), 3501 DG Utrecht, The Netherlands. [3] Interuniversity Cardiology Institute of the Netherlands (ICIN), 3501 DG Utrecht, The Netherlands.
          [235 ] 1] National Institute for Health and Welfare, FI-00271 Helsinki, Finland. [2] Institute for Molecular Medicine, University of Helsinki, FI-00014 Helsinki, Finland. [3] Hjelt Institute Department of Public Health, University of Helsinki, FI-00014 Helsinki, Finland.
          [236 ] 1] Institute of Health Sciences, University of Oulu, FI-90014 Oulu, Finland. [2] Unit of Primary Health Care/General Practice, Oulu University Hospital, FI-90220 Oulu, Finland.
          [237 ] 1] Department for Health Evidence, Radboud University Medical Centre, 6500 HB Nijmegen, The Netherlands. [2] Department of Urology, Radboud University Medical Centre, 6500 HB Nijmegen, The Netherlands.
          [238 ] 1] Ealing Hospital NHS Trust, Middlesex UB1 3HW, UK. [2] National Heart and Lung Institute, Imperial College London, London SW3 6LY, UK. [3] Imperial College Healthcare NHS Trust, London W12 0HS, UK.
          [239 ] 1] Department of Epidemiology and Public Health, University College London, London WC1E 6BT, UK. [2] Department of Biological and Social Epidemiology, University of Essex, Wivenhoe Park, Colchester, Essex CO4 3SQ, UK.
          [240 ] Department of Medicine, Kuopio University Hospital and University of Eastern Finland, FI-70210 Kuopio, Finland.
          [241 ] 1] Kuopio Research Institute of Exercise Medicine, 70100 Kuopio, Finland. [2] Department of Physiology, Institute of Biomedicine, University of Eastern Finland, Kuopio Campus, FI-70211 Kuopio, Finland. [3] Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital and University of Eastern Finland, FI-70210 Kuopio, Finland.
          [242 ] 1] MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK. [2] Department of Epidemiology and Public Health, University College London, London WC1E 6BT, UK.
          [243 ] Department of Clinical Chemistry, Fimlab Laboratories and School of Medicine University of Tampere, FI-33520 Tampere, Finland.
          [244 ] 1] Steno Diabetes Center A/S, Gentofte DK-2820, Denmark. [2] Lund University Diabetes Centre and Department of Clinical Science, Diabetes &Endocrinology Unit, Lund University, Malmö 221 00, Sweden.
          [245 ] 1] Institut Universitaire de Cardiologie et de Pneumologie de Québec, Faculty of Medicine, Laval University, Quebec, QC G1V 0A6, Canada. [2] Institute of Nutrition and Functional Foods, Laval University, Quebec, QC G1V 0A6, Canada.
          [246 ] Department of Genetics, Rutgers University, Piscataway, New Jersey 08854, USA.
          [247 ] Department of Biostatistics, University of Washington, Seattle, Washington 98195, USA.
          [248 ] Department of Surgery, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
          [249 ] 1] Estonian Genome Center, University of Tartu, Tartu 51010, Estonia. [2] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. [3] Department of Biostatistics, University of Liverpool, Liverpool L69 3GA, UK.
          [250 ] Department of Pediatrics, University of Iowa, Iowa City, Iowa 52242, USA.
          [251 ] 1] MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK. [2] MRC Unit for Lifelong Health and Ageing at University College London, London WC1B 5JU, UK.
          [252 ] Illumina, Inc, Little Chesterford, Cambridge CB10 1XL, UK.
          [253 ] 1] Research Unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, D-85764 Neuherberg, Germany. [2] Deutsches Forschungszentrum für Herz-Kreislauferkrankungen (DZHK) (German Research Centre for Cardiovascular Research), Munich Heart Alliance, D-80636 Munich, Germany. [3] Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany, D-85764 Neuherberg, Germany.
          [254 ] University of Groningen, University Medical Center Groningen, Department of Pulmonary Medicine and Tuberculosis, Groningen, The Netherlands.
          [255 ] 1] Center for Biomedicine, European Academy Bozen, Bolzano (EURAC), Bolzano 39100, Italy (affiliated institute of the University of Lübeck, D-23562 Lübeck, Germany). [2] Department of Neurology, General Central Hospital, Bolzano 39100, Italy.
          [256 ] 1] Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. [2] Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
          [257 ] 1] Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, FI-20521 Turku, Finland. [2] Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, FI-20521 Turku, Finland.
          [258 ] Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808, USA.
          [259 ] 1] Department of Genetics, Washington University School of Medicine, St Louis, Missouri 63110, USA. [2] Division of Biostatistics, Washington University School of Medicine, St Louis, Missouri 63110, USA. [3] Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri 63110, USA.
          [260 ] 1] Division of Biostatistics, Washington University School of Medicine, St Louis, Missouri 63110, USA. [2] Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri 63110, USA.
          [261 ] 1] Montreal Heart Institute, Montreal, Quebec H1T 1C8, Canada. [2] Université de Montréal, Montreal, Quebec H1T 1C8, Canada.
          [262 ] Center for Systems Genomics, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.
          [263 ] 1] Centre for Population Health Sciences, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK. [2] Croatian Centre for Global Health, Faculty of Medicine, University of Split, 21000 Split, Croatia.
          [264 ] South Carelia Central Hospital, 53130 Lappeenranta, Finland.
          [265 ] 1] Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, D-01307 Dresden, Germany. [2] Paul Langerhans Institute Dresden, German Center for Diabetes Research (DZD), 01307 Dresden, Germany.
          [266 ] International Centre for Circulatory Health, Imperial College London, London W2 1PG, UK.
          [267 ] 1] Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA. [2] Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA. [3] Geriatric Research and Education Clinical Center, Vetrans Administration Medical Center, Baltimore, Maryland 21201, USA.
          [268 ] Helsinki University Central Hospital Heart and Lung Center, Department of Medicine, Helsinki University Central Hospital, FI-00290 Helsinki, Finland.
          [269 ] 1] Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, D-85764 Neuherberg, Germany. [2] Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, D-81377 Munich, Germany.
          [270 ] 1] Sorbonne Universités, UPMC Univ Paris 06, UMR S 1166, F-75013 Paris, France. [2] INSERM, UMR S 1166, Team Genomics and Physiopathology of Cardiovascular Diseases, F-75013 Paris, France. [3] Institute for Cardiometabolism And Nutrition (ICAN), F-75013 Paris, France.
          [271 ] Department of Kinesiology, Laval University, Quebec QC G1V 0A6, Canada.
          [272 ] Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano &Centro Cardiologico Monzino, Instituto di Ricovero e Cura a Carattere Scientifico, Milan 20133, Italy.
          [273 ] 1] Institute of Nutrition and Functional Foods, Laval University, Quebec, QC G1V 0A6, Canada. [2] Department of Food Science and Nutrition, Laval University, Quebec QC G1V 0A6, Canada.
          [274 ] 1] Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, D-17475 Greifswald, Germany. [2] DZHK (Deutsches Zentrum für Herz-Kreislaufforschung - German Centre for Cardiovascular Research), partner site Greifswald, D-17475 Greifswald, Germany.
          [275 ] Department of Internal Medicine, University Hospital (CHUV) and University of Lausanne, Lausanne 1011, Switzerland.
          [276 ] Department of Epidemiology, Erasmus MC University Medical Center, 3015GE Rotterdam, The Netherlands.
          [277 ] Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
          [278 ] Institut Pasteur de Lille; INSERM, U744; Université de Lille 2; F-59000 Lille, France.
          [279 ] 1] Institute of Cardiovascular Science, University College London, London WC1E 6BT, UK. [2] Durrer Center for Cardiogenetic Research, Interuniversity Cardiology Institute Netherlands (ICIN), 3501 DG Utrecht, The Netherlands. [3] Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
          [280 ] Department of Medicine, Stanford University School of Medicine, Palo Alto, California 94304, USA.
          [281 ] 1] Lee Kong Chian School of Medicine, Imperial College London and Nanyang Technological University, Singapore, 637553 Singapore, Singapore. [2] Department of Internal Medicine I, Ulm University Medical Centre, D-89081 Ulm, Germany.
          [282 ] Health Science Center at Houston, University of Texas, Houston, Texas 77030, USA.
          [283 ] 1] Ealing Hospital NHS Trust, Middlesex UB1 3HW, UK. [2] Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK. [3] Imperial College Healthcare NHS Trust, London W12 0HS, UK.
          [284 ] 1] Department of Medical Genetics, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands. [2] Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. [3] Department of Epidemiology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
          [285 ] 1] Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts 02115, USA. [2] Department of Clinical Sciences, Genetic &Molecular Epidemiology Unit, Lund University Diabetes Center, Skåne University Hosptial, Malmö 205 02, Sweden. [3] Department of Public Health and Clinical Medicine, Unit of Medicine, Umeå University, Umeå 901 87, Sweden.
          [286 ] 1] Department of Genomics of Common Disease, School of Public Health, Imperial College London, Hammersmith Hospital, London W12 0NN, UK. [2] CNRS UMR 8199, F-59019 Lille, France. [3] European Genomic Institute for Diabetes, F-59000 Lille, France. [4] Université de Lille 2, F-59000 Lille, France.
          [287 ] 1] Institute for Molecular Medicine, University of Helsinki, FI-00014 Helsinki, Finland. [2] Lund University Diabetes Centre and Department of Clinical Science, Diabetes &Endocrinology Unit, Lund University, Malmö 221 00, Sweden.
          [288 ] 1] PathWest Laboratory Medicine of Western Australia, Nedlands, Western Australia 6009, Australia. [2] Pathology and Laboratory Medicine, The University of Western Australia, Perth, Western Australia 6009, Australia. [3] School of Population Health, The University of Western Australia, Nedlands, Western Australia 6009, Australia.
          [289 ] 1] Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. [2] Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts 02115, USA. [3] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
          [290 ] Albert Einstein College of Medicine, Department of Epidemiology and Population Health, Belfer 1306, New York 10461, USA.
          [291 ] Department of Epidemiology and Public Health, University College London, London WC1E 6BT, UK.
          [292 ] Center for Human Genetics, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157, USA.
          [293 ] 1] Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, D-68187 Mannheim, Germany. [2] Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz 8036, Austria. [3] Synlab Academy, Synlab Services GmbH, 68163 Mannheim, Germany.
          [294 ] 1] Department of Medicine, Stanford University School of Medicine, Palo Alto, California 94304, USA. [2] Department of Clinical Medicine, Copenhagen University, 2200 Copenhagen, Denmark.
          [295 ] 1] Genetic Epidemiology Unit, Department of Epidemiology, Erasmus MC University Medical Center, 3015 GE Rotterdam, The Netherlands. [2] Center for Medical Sytems Biology, 2300 RC Leiden, The Netherlands. [3] Department of Clinical Genetics, Erasmus MC University Medical Center, 3000 CA Rotterdam, The Netherlands.
          [296 ] 1] Estonian Genome Center, University of Tartu, Tartu 51010, Estonia. [2] National Institute for Health and Welfare, FI-00271 Helsinki, Finland. [3] Institute for Molecular Medicine, University of Helsinki, FI-00014 Helsinki, Finland.
          [297 ] 1] Institute of Nutrition and Functional Foods, Laval University, Quebec, QC G1V 0A6, Canada. [2] Department of Kinesiology, Laval University, Quebec QC G1V 0A6, Canada.
          [298 ] Population, Policy, and Practice, University College London Institute of Child Health, London WC1N 1EH, UK.
          [299 ] 1] Kuopio Research Institute of Exercise Medicine, 70100 Kuopio, Finland. [2] Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital and University of Eastern Finland, FI-70210 Kuopio, Finland.
          [300 ] 1] Finnish Diabetes Association, Kirjoniementie 15, FI-33680 Tampere, Finland. [2] Pirkanmaa Hospital District, FI-33521 Tampere, Finland.
          [301 ] 1] Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK. [2] Center for Non-Communicable Diseases, Karatchi, Pakistan. [3] Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
          [302 ] BHF Glasgow Cardiovascular Research Centre, Division of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8TA, UK.
          [303 ] Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10580, USA.
          [304 ] 1] deCODE Genetics, Amgen Inc., Reykjavik 101, Iceland. [2] Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland.
          [305 ] 1] National Institute for Health and Welfare, FI-00271 Helsinki, Finland. [2] Institute for Health Research, University Hospital of La Paz (IdiPaz), 28046 Madrid, Spain. [3] Diabetes Research Group, King Abdulaziz University, 21589 Jeddah, Saudi Arabia. [4] Centre for Vascular Prevention, Danube-University Krems, 3500 Krems, Austria.
          [306 ] 1] Department of Public Health and Clinical Nutrition, University of Eastern Finland, Finland. [2] Research Unit, Kuopio University Hospital, FI-70210 Kuopio, Finland.
          [307 ] 1] Department of Genetics, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands. [2] Department of Cardiology, University Medical Center Groningen, University of Groningen, 9700RB Groningen, The Netherlands. [3] Durrer Center for Cardiogenetic Research, Interuniversity Cardiology Institute Netherlands (ICIN), 3501 DG Utrecht, The Netherlands.
          [308 ] Institute of Cellular Medicine, Newcastle University, Newcastle NE1 7RU, UK.
          [309 ] 1] DZHK (Deutsches Zentrum für Herz-Kreislaufforschung - German Centre for Cardiovascular Research), partner site Greifswald, D-17475 Greifswald, Germany. [2] Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, D-17475 Greifswald, Germany.
          [310 ] 1] Institute of Medical Informatics, Biometry and Epidemiology, Chair of Epidemiology, Ludwig-Maximilians-Universität, D-85764 Munich, Germany. [2] Klinikum Grosshadern, D-81377 Munich, Germany. [3] Institute of Epidemiology I, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany, D-85764 Neuherberg, Germany.
          [311 ] Department of Pulmonology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
          [312 ] 1] Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK. [2] William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK. [3] Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, 21589 Jeddah, Saudi Arabia.
          [313 ] National Heart, Lung, and Blood Institute, the Framingham Heart Study, Framingham, Massachusetts 01702, USA.
          [314 ] 1] Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University of Regensburg, D-93053 Regensburg, Germany. [2] Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, D-85764 Neuherberg, Germany.
          [315 ] 1] Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA. [2] Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
          [316 ] Division of Population Health Sciences &Education, St George's, University of London, London SW17 0RE, UK.
          [317 ] 1] Genetic Epidemiology Unit, Department of Epidemiology, Erasmus MC University Medical Center, 3015 GE Rotterdam, The Netherlands. [2] Netherlands Consortium for Healthy Aging (NCHA), 3015GE Rotterdam, The Netherlands. [3] Department of Epidemiology, Erasmus MC University Medical Center, 3015GE Rotterdam, The Netherlands. [4] Center for Medical Sytems Biology, 2300 RC Leiden, The Netherlands.
          [318 ] 1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. [2] Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LJ, UK. [3] Oxford NIHR Biomedical Research Centre, Oxford University Hospitals NHS Trust, Oxford OX3 7LJ, UK.
          [319 ] 1] Institute for Medical Informatics, Biometry and Epidemiology (IMIBE), University Hospital Essen, 45147 Essen, Germany. [2] Clinical Epidemiology, Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, 07743 Jena, Germany.
          [320 ] 1] Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA. [2] Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan 48109, USA. [3] Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.
          [321 ] 1] Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA. [2] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
          [322 ] 1] Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland. [2] Department of Medical Genetics, University of Lausanne, Lausanne 1005, Switzerland. [3] Service of Medical Genetics, CHUV University Hospital, 1011 Lausanne, Switzerland.
          [323 ] 1] Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK. [2] University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 OQQ, UK. [3] NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 OQQ, UK.
          [324 ] 1] Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA. [2] Carolina Center for Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
          [325 ] 1] MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK. [2] The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA. [3] The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA. [4] The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
          Article
          nature14177 NIHMS668049
          10.1038/nature14177
          4382211
          25673413
          06080a69-06ad-483a-9ce7-77bc0806e073
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