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      The genetic architecture of type 2 diabetes

      research-article
      1 , 2 , 3 , 4 , 5 , 1 , 6 , 4 , 7 , 6 , 1 , 4 , 6 , 6 , 8 , 6 , 6 , 9 , 10 , 11 , 1 , 1 , 6 , 12 , 6 , 12 , 13 , 14 , 15 , 1 , 6 , 16 , 17 , 18 , 19 , 4 , 6 , 4 , 1 , 17 , 20 , 1 , 6 , 12 , 6 , 6 , 21 , 22 , 23 , 24 , 25 , 26 , 1 , 27 , 28 , 6 , 10 , 29 , 30 , 31 , 32 , 33 , 9 , 34 , 35 , 4 , 12 , 13 , 6 , 36 , 6 , 12 , 37 , 28 , 38 , 39 , 40 , 32 , 28 , 32 , 41 , 32 , 28 , 1 , 29 , 15 , 42 , 43 , 30 , 1 , 41 , 44 , 45 , 46 , 47 , 48 , 32 , 49 , 50 , 51 , 51 , 52 , 4 , 53 , 54 , 53 , 54 , 55 , 56 , 51 , 49 , 57 , 58 , 59 , 60 , 61 , 4 , 1 , 4 , 62 , 4 , 63 , 64 , 4 , 64 , 65 , 66 , 66 , 67 , 60 , 68 , 69 , 13 , 66 , 70 , 67 , 68 , 71 , 72 , 73 , 67 , 67 , 44 , 74 , 75 , 38 , 39 , 40 , 76 , 77 , 78 , 79 , 30 , 38 , 39 , 40 , 80 , 81 , 82 , 17 , 83 , 49 , 84 , 85 , 75 , 53 , 54 , 55 , 30 , 38 , 39 , 86 , 87 , 82 , 44 , 88 , 30 , 30 , 87 , 89 , 44 , 90 , 91 , 92 , 83 , 44 , 88 , 45 , 61 , 81 , 49 , 93 , 38 , 39 , 40 , 94 , 95 , 12 , 11 , 19 , 96 , 97 , 11 , 98 , 99 , 12 , 96 , 26 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 103 , 4 , 108 , 109 , 110 , 111 , 104 , 112 , 113 , 11 , 97 , 97 , 26 , 114 , 115 , 116 , 117 , 97 , 26 , 118 , 119 , 99 , 120 , 121 , 122 , 58 , 123 , 19 , 115 , 124 , 125 , 126 , 108 , 12 , 127 , 128 , 129 , 130 , 129 , 131 , 98 , 99 , 132 , 133 , 19 , 97 , 13 , 9 , 108 , 134 , 4 , 4 , 4 , 4 , 4 , 4 , 99 , 135 , 136 , 137 , 138 , 26 , 1 , 29 , 139 , 4 , 4 , 99 , 120 , 26 , 140 , 99 , 120 , 31 , 129 , 112 , 141 , 12 , 127 , 20 , 31 , 25 , 99 , 120 ,   99 , 120 , 142 , 143 , 26 , 144 , 103 , 145 , 146 , 147 , 148 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 60 , 155 , 156 , 67 , 157 , 158 , 30 , 63 , 59 , 10 , 44 , 159 , 160 , 49 , 37 , 67 , 157 , 158 , 161 , 13 , 66 , 162 , 88 , 163 , 13 , 142 , 30 , 164 , 165 , 13 , 60 , 11 , 22 , 49 , 99 , 120 , 121 , 166 , 108 , 10 , 167 , 4 , 22 , 120 , 121 , 6 , 168 , 27 , 121 , 169 , 170 , 35 , 129 , 133 , 134 , 134 , 134 , 6 , 12 , 163 , 108 , 171 , 172 , 12 , 127 , 6 , 12 , 127 , 22 , 24 , 104 , 112 , 113 , 173 , 45 , 61 , 174 , 32 , 28 , 41 , 6 , 8 , 175 , 176 , 177 , 53 , 54 , 55 , 19 , 46 , 178 , 44 , 45 , 174 , 11 , 51 , 52 , 96 , 179 , 180 , 82 , 83 , 30 , 76 , 181 , 6 , 182 , 29 , 183 , 184 , 185 , 9 , 186 , 27 , 15 , 42 , 187 , 188 , 4 , 4 , 189 , 96 , 179 , 97 , 173 , 1 , 4 , 64 , 190 , 191 , 1 , 6 , 108 , 192 , 1 , 1 , 4 , 5 , 109 , 190 , 191 , 193 , 6 , 12 , 127
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          Abstract

          The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of heritability. To test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole genome sequencing in 2,657 Europeans with and without diabetes, and exome sequencing in a total of 12,940 subjects from five ancestral groups. To increase statistical power, we expanded sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support a major role for lower-frequency variants in predisposition to type 2 diabetes.

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          Most cited references38

          • Record: found
          • Abstract: found
          • Article: not found

          Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis.

          By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P<5x10(-8). These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits.
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            • Record: found
            • Abstract: found
            • Article: not found

            Detecting overlapping protein complexes in protein-protein interaction networks.

            We introduce clustering with overlapping neighborhood expansion (ClusterONE), a method for detecting potentially overlapping protein complexes from protein-protein interaction data. ClusterONE-derived complexes for several yeast data sets showed better correspondence with reference complexes in the Munich Information Center for Protein Sequence (MIPS) catalog and complexes derived from the Saccharomyces Genome Database (SGD) than the results of seven popular methods. The results also showed a high extent of functional homogeneity.
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              • Record: found
              • Abstract: found
              • Article: not found

              Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease

              Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver disease. To elucidate the molecular basis of NAFLD we performed an exome-wide association study of liver fat content. Three variants were associated with increased liver fat at the exome-wide significance level: two in PNPLA3, an established locus for NAFLD, and one (Glu167Lys) in TM6SF2, a gene of unknown function. The Glu167LysTM6SF2 variant was also associated with higher circulating levels of alanine transaminase, a marker of liver injury, and lower levels of LDL-cholesterol, triglycerides and alkaline phosphatase in 3 independent populations (n>80,000). Recombinant Glu167LysTM6SF2 produced 50% less protein than wild-type TM6SF2 when expressed in cultured hepatocytes. Adeno-associated virus-mediated shRNA knockdown of Tm6sf2 in mice increased liver triglyceride content 3-fold and decreased VLDL secretion by 50%. Taken together, these data indicate that TM6SF2 activity is required for normal VLDL secretion, and that impaired TM6SF2 function causally contributes to NAFLD.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                13 September 2016
                4 August 2016
                04 February 2017
                : 536
                : 7614
                : 41-47
                Affiliations
                [1 ]Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA
                [2 ]Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
                [3 ]Center for Biomedicine, European Academy of Bolzano/Bozen (EURAC), affiliated with the University of Lübeck, Bolzano, Italy
                [4 ]Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA
                [5 ]Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA
                [6 ]Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK
                [7 ]Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
                [8 ]Department of Statistics, University of Oxford, Oxford, UK
                [9 ]Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK
                [10 ]MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK
                [11 ]Department of Twin Research and Genetic Epidemiology, King's College London, London, UK
                [12 ]Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
                [13 ]Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, UK
                [14 ]School of Computer Science, McGill University, Montreal, Quebec, Canada
                [15 ]McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada
                [16 ]Human Genetics Center, The University of Texas Graduate School of Biomedical Sciences at Houston, The University of Texas Health Science Center at Houston, Houston, Texas, USA
                [17 ]Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA
                [18 ]National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA
                [19 ]Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA
                [20 ]Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA
                [21 ]Chronic Disease Epidemiology, Swiss Tropical and Public Health Institute, University of Basel, Basel, Switzerland
                [22 ]Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
                [23 ]Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany
                [24 ]Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany
                [25 ]DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
                [26 ]The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
                [27 ]Department of Medicine, Section of Genetic Medicine, The University of Chicago, Chicago, Illinois, USA
                [28 ]Department of Statistics, Seoul National University, Seoul, Republic of Korea
                [29 ]Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, USA
                [30 ]Saw Swee Hock School of Public Health, National University of Singapore, National University Health System, Singapore
                [31 ]Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA
                [32 ]Center for Genome Science, Korea National Institute of Health, Chungcheongbuk-do, Republic of Korea
                [33 ]The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA
                [34 ]Departments of Computational Medicine & Bioinformatics and Human Genetics, University of Michigan, Ann Arbor, Michigan, USA
                [35 ]Department of Clinical Sciences, Lund University Diabetes Centre, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden
                [36 ]Department of Epidemiology, Colorado School of Public Health, University of Colorado, Aurora, Colorado, USA
                [37 ]Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
                [38 ]Singapore Eye Research Institute, Singapore National Eye Centre, Singapore
                [39 ]Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore
                [40 ]The Eye Academic Clinical Programme, Duke-NUS Graduate Medical School, Singapore
                [41 ]Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul, Republic of Korea
                [42 ]Department of Human Genetics, McGill University, Montreal, Quebec, Canada
                [43 ]Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
                [44 ]Department of Epidemiology and Biostatistics, Imperial College London, London, UK
                [45 ]Department of Cardiology, Ealing Hospital NHS Trust, Southall, Middlesex, UK
                [46 ]Departments of Medicine and Genetics, Albert Einstein College of Medicine, New York, USA
                [47 ]Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania - Perelman School of Medicine, Philadelphia, Pennsylvania, USA
                [48 ]Department of Genetics, University of Pennsylvania - Perelman School of Medicine, Philadelphia, Pennsylvania, USA
                [49 ]Department of Medicine, University of Texas Health Science Center, San Antonio, Texas, USA
                [50 ]Research, South Texas Veterans Health Care System, San Antonio, Texas, USA
                [51 ]Faculty of Health Sciences, Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland
                [52 ]Kuopio University Hospital, Kuopio, Finland
                [53 ]Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
                [54 ]Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
                [55 ]Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
                [56 ]Centre for Research in Epidemiology and Population Health, Inserm U1018, Villejuif, France
                [57 ]German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
                [58 ]Department of Public Health and Caring Sciences, Geriatrics, Uppsala University, Uppsala, Sweden
                [59 ]Centre for Chronic Disease Control, New Delhi, India
                [60 ]The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, USA
                [61 ]National Heart and Lung Institute, Cardiovascular Sciences, Hammersmith Campus, Imperial College London, London, UK
                [62 ]Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA
                [63 ]Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
                [64 ]Center for Human Genetic Research, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
                [65 ]Department of Psychiatry, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, USA
                [66 ]Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
                [67 ]Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
                [68 ]Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
                [69 ]Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
                [70 ]NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
                [71 ]Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, and College of Medicine, Seoul National University, Seoul, Republic of Korea
                [72 ]Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
                [73 ]Center for Non-Communicable Diseases, Karachi, Pakistan
                [74 ]Cardiovascular Division, Baylor College of Medicine, Houston, Texas, USA
                [75 ]Department of Pediatrics, University of Texas Health Science Center, San Antonio, Texas, USA
                [76 ]Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore
                [77 ]Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia, Spain
                [78 ]CIBER Epidemiología y Salud Pública (CIBERESP), Spain
                [79 ]Unit of Preventive Medicine and Public Health, School of Medicine, University of Murcia, Spain
                [80 ]Cancer Research and Prevention Institute (ISPO), Florence, Italy
                [81 ]Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA
                [82 ]South Texas Diabetes and Obesity Institute, Regional Academic Health Center, University of Texas Rio Grande Valley, Brownsville, Texas, USA
                [83 ]Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas, USA
                [84 ]Department of Internal Medicine, Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
                [85 ]Center of Biostatistics and Bioinformatics, University of Mississippi Medical Center, Jackson, Mississippi, USA
                [86 ]Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore
                [87 ]Division of Human Genetics, Genome Institute of Singapore, A*STAR, Singapore
                [88 ]CNRS-UMR8199, Lille University, Lille Pasteur Institute, Lille, France
                [89 ]Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands
                [90 ]Institute of Health Sciences, University of Oulu, Oulu, Finland
                [91 ]Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
                [92 ]Jackson Heart Study, University of Mississippi Medical Center, Jackson, Mississippi, USA
                [93 ]College of Public Services, Jackson State University, Jackson, Mississippi, USA
                [94 ]KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway
                [95 ]Department of Pediatrics, Haukeland University Hospital, Bergen, Norway
                [96 ]Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
                [97 ]Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Malmö, Sweden
                [98 ]Institute of Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
                [99 ]German Center for Diabetes Research (DZD), Neuherberg, Germany
                [100 ]Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark
                [101 ]Department of Clinical Biochemistry, Vejle Hospital, Vejle, Denmark
                [102 ]Department of Internal Medicine and Endocrinology, Vejle Hospital, Vejle, Denmark
                [103 ]Department of Health, National Institute for Health and Welfare, Helsinki, Finland
                [104 ]Abdominal Center: Endocrinology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
                [105 ]Minerva Foundation Institute for Medical Research, Helsinki, Finland
                [106 ]Department of Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
                [107 ]Division of Cardiovascular and Diabetes Medicine, Medical Research Institute, Ninewells Hospital and Medical School, Dundee, UK
                [108 ]Estonian Genome Center, University of Tartu, Tartu, Estonia
                [109 ]Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA
                [110 ]Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA
                [111 ]Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK
                [112 ]Folkhälsan Research Centre, Helsinki, Finland
                [113 ]Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland
                [114 ]Steno Diabetes Center, Gentofte, Denmark
                [115 ]Research Centre for Prevention and Health, Capital Region of Denmark, Glostrup, Denmark
                [116 ]Department of Public Health, Institute of Health Sciences, University of Copenhagen, Copenhagen, Denmark
                [117 ]Faculty of Medicine, Aalborg University, Aalborg, Denmark
                [118 ]Department of Primary Health Care, Vaasa Central Hospital, Vaasa, Finland
                [119 ]Diabetes Center, Vaasa Health Care Center, Vaasa, Finland
                [120 ]Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
                [121 ]Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
                [122 ]Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
                [123 ]Department of Public Health, Section of General Practice, Aarhus University, Aarhus, Denmark
                [124 ]Department of Clinical Experimental Research, Rigshospitalet, Glostrup, Denmark
                [125 ]Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
                [126 ]Department of Clinical Sciences, Hypertension and Cardiovascular Disease, Lund University, Malmö, Sweden
                [127 ]Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, UK
                [128 ]Department of Clinical Sciences, Diabetes and Cardiovascular Disease, Genetic Epidemiology, Lund University, Malmö, Sweden
                [129 ]Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA
                [130 ]Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
                [131 ]Department of Epidemiology and Population Health, Albert Einstein College of Medicine, New York, USA
                [132 ]Department of Endocrinology and Diabetology, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany
                [133 ]Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
                [134 ]High Throughput Genomics, Oxford Genomics Centre, Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK
                [135 ]Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
                [136 ]Center of Life and Food Sciences Weihenstephan, Technische Universität München, Freising-Weihenstephan, Germany
                [137 ]William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
                [138 ]Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia
                [139 ]Department of Clinical Sciences, Medicine, Lund University, Malmö, Sweden
                [140 ]Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
                [141 ]Department of Social Services and Health Care, Jakobstad, Finland
                [142 ]Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, UK
                [143 ]Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK
                [144 ]Foundation for Research in Health, Exercise and Nutrition, Kuopio Research Institute of Exercise Medicine, Kuopio, Finland
                [145 ]Center for Vascular Prevention, Danube University Krems, Krems, Austria
                [146 ]Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia
                [147 ]Instituto de Investigacion Sanitaria del Hospital Universario LaPaz (IdiPAZ), University Hospital LaPaz, Autonomous University of Madrid, Madrid, Spain
                [148 ]National Institute for Health and Welfare, Helsinki, Finland
                [149 ]Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
                [150 ]Department of Physiology & Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
                [151 ]Diabetes and Obesity Research Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
                [152 ]Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
                [153 ]Cedars-Sinai Diabetes and Obesity Research Institute, Los Angeles, California, USA
                [154 ]Functional Genomics Unit, CSIR-Institute of Genomics & Integrative Biology (CSIR-IGIB), New Delhi, India
                [155 ]Department of Biomedical Science, Hallym University, Chuncheon, Republic of Korea
                [156 ]CSIR-Centre for Cellular and Molecular Biology, Hyderabad, Telangana, India
                [157 ]Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
                [158 ]Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, China
                [159 ]MRC-PHE Centre for Environment and Health, Imperial College London, London, UK
                [160 ]The Biostatistics Center, The George Washington University, Rockville, Maryland, USA
                [161 ]Department of Medicine, Division of Endocrinology, Diabetes and Nutrition, and Program in Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA
                [162 ]Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, New Delhi, India
                [163 ]Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, UK
                [164 ]Life Sciences Institute, National University of Singapore, Singapore
                [165 ]Department of Statistics and Applied Probability, National University of Singapore, Singapore
                [166 ]Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
                [167 ]The Medical School, Institute of Cellular Medicine, Newcastle University, Newcastle, UK
                [168 ]Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
                [169 ]Hannover Unified Biobank, Hannover Medical School, Hanover, Germany
                [170 ]Institute for Human Genetics, Hannover Medical School, Hanover, Germany
                [171 ]Department of Medical Sciences, Uppsala University, Uppsala, Sweden
                [172 ]Data Sciences and Data Engineering, Broad Institute, Cambridge, Massachusetts, USA
                [173 ]Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
                [174 ]Imperial College Healthcare NHS Trust, Imperial College London, London, UK
                [175 ]Clinical Research Centre, Centre for Molecular Medicine, Ninewells Hospital and Medical School, Dundee, UK
                [176 ]The Usher Institute to the Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK
                [177 ]University of Exeter Medical School, University of Exeter, Exeter, UK
                [178 ]Department of Natural Science, University of Haifa, Haifa, Israel
                [179 ]Institute of Human Genetics, Technische Universität München, Munich, Germany
                [180 ]Departments of Medicine and Human Genetics, The University of Chicago, Chicago, Illinois, USA
                [181 ]Cardiovascular & Metabolic Disorders Program, Duke-NUS Medical School Singapore, Singapore
                [182 ]Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK
                [183 ]Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA
                [184 ]Department of Laboratory Medicine & Institute for Human Genetics, University of California, San Francisco, San Francisco, California, USA
                [185 ]Blood Systems Research Institute, San Francisco, California, USA
                [186 ]General Medicine Division, Massachusetts General Hospital and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
                [187 ]Division of Endocrinology and Metabolism, Department of Medicine, McGill University, Montreal, Quebec, Canada
                [188 ]Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
                [189 ]Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA
                [190 ]Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
                [191 ]Diabetes Research Center (Diabetes Unit), Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
                [192 ]Department of Biostatistics, University of Liverpool, Liverpool, UK
                [193 ]Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
                Author notes
                Correspondence and request for materials should be addressed to mark.mccarthy@ 123456drl.ox.ac.uk or boehnke@ 123456umich.edu .
                [†]

                These authors jointly supervised this work.

                [‡]

                Deceased.

                Current addresses (where relevant) are provided in supplementary information.

                Article
                EMS68809
                10.1038/nature18642
                5034897
                27398621
                5fb740f3-7b83-424f-92ef-4f90222850df

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