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      An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans

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

          Abstract

          To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci ( P < 5 × 10 −8), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action–associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.

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          Most cited references13

          • 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
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            • Article: not found

            Gut hormones and the regulation of energy homeostasis.

            Food intake, energy expenditure and body adiposity are homeostatically regulated. Central and peripheral signals communicate information about the current state of energy balance to key brain regions, including the hypothalamus and brainstem. Hunger and satiety represent coordinated responses to these signals, which include neural and hormonal messages from the gut. In recent years our understanding of how neural and hormonal brain-gut signalling regulates energy homeostasis has advanced considerably. Gut hormones have various physiological functions that include specifically targeting the brain to regulate appetite. New research suggests that gut hormones can be used to specifically regulate energy homeostasis in humans, and offer a target for anti-obesity drugs.
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              • Abstract: found
              • Article: not found

              Identification of low-frequency and rare sequence variants associated with elevated or reduced risk of type 2 diabetes.

              Through whole-genome sequencing of 2,630 Icelanders and imputation into 11,114 Icelandic cases and 267,140 controls followed by testing in Danish and Iranian samples, we discovered 4 previously unreported variants affecting risk of type 2 diabetes (T2D). A low-frequency (1.47%) variant in intron 1 of CCND2, rs76895963[G], reduces risk of T2D by half (odds ratio (OR) = 0.53, P = 5.0 × 10(-21)) and is correlated with increased CCND2 expression. Notably, this variant is also associated with both greater height and higher body mass index (1.17 cm per allele, P = 5.5 × 10(-12) and 0.56 kg/m(2) per allele, P = 6.5 × 10(-7), respectively). In addition, two missense variants in PAM, encoding p.Asp563Gly (frequency of 4.98%) and p.Ser539Trp (frequency of 0.65%), confer moderately higher risk of T2D (OR = 1.23, P = 3.9 × 10(-10) and OR = 1.47, P = 1.7 × 10(-5), respectively), and a rare (0.20%) frameshift variant in PDX1, encoding p.Gly218Alafs*12, associates with high risk of T2D (OR = 2.27, P = 7.3 × 10(-7)).
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                Author and article information

                Journal
                Diabetes
                Diabetes
                diabetes
                diabetes
                Diabetes
                Diabetes
                American Diabetes Association
                0012-1797
                1939-327X
                November 2017
                31 May 2017
                : 66
                : 11
                : 2888-2902
                Affiliations
                [1] 1MRC Epidemiology Unit, University of Cambridge, Cambridge, U.K.
                [2] 2Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI
                [3] 3Estonian Genome Center, University of Tartu, Tartu, Estonia
                [4] 4Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy
                [5] 5Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.
                [6] 6Department of Genetics, Stanford University, Stanford, CA
                [7] 7Department of Genomics of Common Disease, Imperial College London, London, U.K.
                [8] 8Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA
                [9] 9Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children’s Hospital, Boston, MA
                [10] 10Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
                [11] 11Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
                [12] 12Framingham Heart Study, Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Framingham, MA
                [13] 13deCODE genetics, Amgen, Inc., Reykjavik, Iceland
                [14] 14Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA
                [15] 15Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA
                [16] 16Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
                [17] 17Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics and Biomedical Research Institute, Ninewells Hospital, University of Dundee, Dundee, U.K.
                [18] 18Human Genetics Center and Department of Epidemiology, Human Genetics & Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX
                [19] 19Center for Precision Health, School Biomedical Informatics, and School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX
                [20] 20Lund University Diabetes Centre and Department of Clinical Sciences Malmö, University Hospital Scania, Lund University, Malmö, Sweden
                [21] 21Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
                [22] 22Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
                [23] 23Institute of Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
                [24] 24Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
                [25] 25Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
                [26] 26German Center for Diabetes Research, Neuherberg, Germany
                [27] 27Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
                [28] 28Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany
                [29] 29Genetic Epidemiology, Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany
                [30] 30Munich Heart Alliance, German Centre for Cardiovascular Disease, Munich, Germany
                [31] 31Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K.
                [32] 32Wellcome Trust Sanger Institute, Hinxton, U.K.
                [33] 33Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands
                [34] 34PolyOmica, 's-Hertogenbosch, the Netherlands
                [35] 35High Throughput Biology Center, Johns Hopkins University School of Medicine, Baltimore, MD
                [36] 36Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
                [37] 37The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
                [38] 38The Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, NY
                [39] 39l'institut du thorax, INSERM, CNRS, Centre Hospitalier Universitaire de Nantes, Université de Nantes, Nantes, France
                [40] 40Lille Institute of Biology, European Genomics Institute of Diabetes, Lille, France
                [41] 41CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, Lille, France
                [42] 42Leibniz Institute on Aging, Fritz Lipmann Institute, Jena, Germany
                [43] 43Institute of Medical Systems Biology, Ulm University, Ulm, Germany
                [44] 44Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
                [45] 45Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, Essen, Germany
                [46] 46Molecular Epidemiology, Department of Medical Sciences, and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
                [47] 47Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
                [48] 48Science for Life Laboratory, Stockholm, Sweden
                [49] 49Department for Numerical Analysis and Computer Science, Stockholm University, Stockholm, Sweden
                [50] 50Faculty of Medicine, University of Iceland, Reykjavik, Iceland
                [51] 51Landspítali University Hospital, Reykjavik, Iceland
                [52] 52Icelandic Heart Association, Kópavogur, Iceland
                [53] 53Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA
                [54] 54Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany
                [55] 55Institute of Human Genetics, Technische Universität München, Munich, Germany
                [56] 56Department of Endocrinology and Diabetology, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany
                [57] 57Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
                [58] 58Division of Genetics and Endocrinology, Boston Children's Hospital, Boston, MA
                [59] 59Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, MA
                [60] 60Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
                [61] 61Department of Biostatistics, Boston University School of Public Health, Boston, MA
                [62] 62Data Coordinating Center, Boston University School of Public Health, Boston, MA
                [63] 63Folkhälsan Research Center, Helsinki, Finland
                [64] 64Department of Social Services and Health Care, Jakobstad, Finland
                [65] 65Department of Medicine, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
                [66] 66Collaborative Studies Coordinating Center, Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC
                [67] 67Division of Epidemiology & Community Health, University of Minnesota, Minneapolis, MN
                [68] 68Steno Diabetes Center, Gentofte, Denmark
                [69] 69Research Centre for Prevention and Health, Capital Region of Denmark, Copenhagen, Denmark
                [70] 70Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
                [71] 71Faculty of Medicine, Aalborg University, Aalborg, Denmark
                [72] 72Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
                [73] 73Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
                [74] 74Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL
                [75] 75Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore
                [76] 76Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA
                [77] 77National Institute for Health Research Oxford Biomedical Research Centre, Churchill Hospital, Oxford, U.K.
                [78] 78Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, U.K.
                [79] 79National Human Genome Research Institute, National Institutes of Health, Bethesda, MD
                [80] 80Department of Health, National Institute for Health and Welfare, Helsinki, Finland
                [81] 81Endocrinology, Department of Medicine and Abdominal Center, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
                [82] 82Minerva Foundation Institute for Medical Research, Biomedicum Helsinki 2U, Helsinki, Finland
                [83] 83Institute of Human Genetics, University of Bonn, Bonn, Germany
                [84] 84Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany
                [85] 85Centro Cardiologico Monzino, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
                [86] 86Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Milan, Italy
                [87] 87Cardiovascular Genetics, BHF Laboratories, Institute Cardiovascular Sciences, University College London, London, U.K.
                [88] 88Hannover Unified Biobank, Hannover Medical School, Hannover, Germany
                [89] 89Department of Clinical Chemistry and Central Laboratory, University of Ulm, Ulm, Germany
                [90] 90Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands
                [91] 91Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland
                [92] 92Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland
                [93] 93Unit of General Practice, Helsinki University Central Hospital, Helsinki, Finland
                [94] 94Broad Institute of MIT and Harvard, Cambridge, MA
                [95] 95Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland
                [96] 96Endocrinology-Diabetology Unit, Corbeil-Essonnes Hospital, Corbeil-Essonnes, France
                [97] 97Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
                [98] 98Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY
                [99] 99IFB AdiposityDiseases, University of Leipzig, Leipzig, Germany
                [100] 100Department of Medicine, University of Leipzig, Leipzig, Germany
                [101] 101Division of General Internal Medicine, Department of Medicine, Johns Hopkins Bloomberg School of Medicine, Baltimore, MD
                [102] 102The Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins University, Baltimore, MD
                [103] 103William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University London, London, U.K.
                [104] 104Department of Statistics, University of Oxford, Oxford, U.K.
                [105] 105Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K.
                [106] 106Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland
                [107] 107Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
                [108] 108Division of Endocrinology and Diabetes, Department of Internal Medicine, University Medical Centre Ulm, Ulm, Germany
                [109] 109Lee Kong Chian School of Medicine, Imperial College London and Nanyang Technological University, Singapore, Singapore
                [110] 110Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA
                [111] 111Department of Genetics, University of North Carolina, Chapel Hill, NC
                [112] 112Dasman Diabetes Institute, Dasman, Kuwait
                [113] 113Centre for Vascular Prevention, Danube University Krems, Krems, Austria
                [114] 114Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia
                [115] 115Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
                [116] 116University of Cambridge Metabolic Research Laboratories and National Institute for Health Research Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital Cambridge, Cambridge, U.K.
                [117] 117Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden
                [118] 118Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA
                [119] 119Cardiovascular Epidemiology, Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden
                [120] 120The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY
                [121] 121INSERM, CESP, UMR 1018, Villejuif, France
                [122] 122University of Paris-Sud, UMR 1018, Villejuif, France
                [123] 123German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
                [124] 124Lund University, Malmö, Sweden
                [125] 125Umeå University, Umeå, Sweden
                [126] 126Navarra Public Health Institute, Pamplona, Spain
                [127] 127Navarra Institute for Health Research, Pamplona, Spain
                [128] 128CIBER Epidemiology and Public Health, Madrid, Spain
                [129] 129Cancer Research and Prevention Institute, Florence, Italy
                [130] 130University Medical Center Utrecht, Utrecht, the Netherlands
                [131] 131Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA
                [132] 132Department of Medicine, Harvard Medical School, Boston, MA
                [133] 133Department of Genetics, Harvard Medical School, Boston, MA
                [134] 134Department of Molecular Biology, Harvard Medical School, Boston, MA
                [135] 135Diabetes Unit, Massachusetts General Hospital, Boston, MA
                [136] 136Netherlands Genomics Initiative, Netherlands Consortium for Healthy Ageing and Center for Medical Systems Biology, Rotterdam, the Netherlands
                [137] 137Diabetes Unit and Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA
                [138] 138General Medicine Division, Massachusetts General Hospital, Boston, MA
                [139] 139Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, TX
                [140] 140Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX
                [141] 141Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia
                [142] 142Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, Edinburgh, U.K.
                [143] 143Cardiovascular and Diabetes Medicine, Biomedical Research Institute, Ninewells Hospital, University of Dundee, Dundee, U.K.
                [144] 144Department of Biostatistics, University of Liverpool, Liverpool, U.K.
                [145] 145Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, U.K.
                Author notes
                Corresponding authors: Inga Prokopenko, i.prokopenko@ 123456imperial.ac.uk ,
                Mark I. McCarthy, mark.mccarthy@ 123456drl.ox.ac.uk , and
                Michael Boehnke, boehnke@ 123456umich.edu .

                R.A.S., L.J.S., R.M., L.M., K.J.G., and M.K. contributed equally to this work. A.P.M., M.Bo., M.I.M., and I.P. jointly directed this research.

                Author information
                http://orcid.org/0000-0001-8200-6382
                http://orcid.org/0000-0002-8306-6202
                http://orcid.org/0000-0003-1624-7457
                Article
                1253
                10.2337/db16-1253
                5652602
                28566273
                bb0a9dd8-a248-437c-8800-e01898ee3a4e
                © 2017 by the American Diabetes Association.

                Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.

                History
                : 27 October 2016
                : 21 May 2017
                Page count
                Figures: 3, Tables: 1, Equations: 0, References: 51, Pages: 15
                Categories
                0409
                Genetics/Genomes/Proteomics/Metabolomics

                Endocrinology & Diabetes
                Endocrinology & Diabetes

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