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

Robert A Scott 1, Laura J Scott 2, Reedik Mägi 3, Letizia Marullo 4, Kyle J Gaulton 5 6, Marika Kaakinen 7, Natalia Pervjakova 3, Tune H Pers 8 9 10 11, Andrew D Johnson 12, John D Eicher 12, Anne U Jackson 2, Teresa Ferreira 5, Yeji Lee 2, Clement Ma 2, Valgerdur Steinthorsdottir 13, Gudmar Thorleifsson 13, Lu Qi 14 15 16, Natalie R Van Zuydam 5 17, Anubha Mahajan 5, Han Chen 18 19, Peter Almgren 20, Ben F Voight 21 22 23, Harald Grallert 24 25 26, Martina Müller-Nurasyid 27 28 29 30, Janina S Ried 27, Nigel W Rayner 5 31 32, Neil Robertson 5 31, Lennart C Karssen 33 34, Elisabeth M van Leeuwen 33, Sara M Willems 1 33, Christian Fuchsberger 2, Phoenix Kwan 2, Tanya M Teslovich 2, Pritam Chanda 35, Man Li 36, Yingchang Lu 37 38, Christian Dina 39, Dorothee Thuillier 40 41, Loic Yengo 40 41, Longda Jiang 7, Thomas Sparso 10, Hans A Kestler 42 43, Himanshu Chheda 44, Lewin Eisele 45, Stefan Gustafsson 46, Mattias Frånberg 47 48 49, Rona J Strawbridge 47, Rafn Benediktsson 50 51, Astradur B Hreidarsson 51, Augustine Kong 13, Gunnar Sigurðsson 51 52, Nicola D Kerrison 1, Jian'an Luan 1, Liming Liang 14 53, Thomas Meitinger 30 54 55, Michael Roden 26 56 57, Barbara Thorand 25 26, Tõnu Esko 3 8 58, Evelin Mihailov 3, Caroline Fox 59 60, Ching-Ti Liu 61, Denis Rybin 62, Bo Isomaa 63 64, Valeriya Lyssenko 20, Tiinamaija Tuomi 63 65, David J Couper 66, James S Pankow 67, Niels Grarup 10, Christian T Have 10, Marit E Jørgensen 68, Torben Jørgensen 69 70 71, Allan Linneberg 69 72 73, Marilyn C Cornelis 74, Rob M van Dam 15 75, David J Hunter 14 15 16 76, Peter Kraft 14 53 76, Qi Sun 15 16, Sarah Edkins 32, Katharine R Owen 31 77, John R B Perry 1, Andrew R Wood 78, Eleftheria Zeggini 32, Juan Tajes-Fernandes 5, Goncalo R Abecasis 2, Lori L Bonnycastle 79, Peter S Chines 79, Heather M Stringham 2, Heikki A Koistinen 80 81 82, Leena Kinnunen 80 81 82, Bengt Sennblad 47 48, Thomas W Mühleisen 83 84, Markus M Nöthen 83 84, Sonali Pechlivanis 45, Damiano Baldassarre 85 86, Karl Gertow 47, Steve E Humphries 87, Elena Tremoli 85 86, Norman Klopp 24 88, Julia Meyer 27, Gerald Steinbach 89, Roman Wennauer 90, Johan G Eriksson 63 91 92 93, Satu Mӓnnistö 91, Leena Peltonen 32 44 91 94, Emmi Tikkanen 44 95, Guillaume Charpentier 96, Elodie Eury 41, Stéphane Lobbens 41, Bruna Gigante 97, Karin Leander 97, Olga McLeod 47, Erwin P Bottinger 37, Omri Gottesman 37, Douglas Ruderfer 98, Matthias Blüher 99 100, Peter Kovacs 99 100, Anke Tonjes 99 100, Nisa M Maruthur 36 101 102, Chiara Scapoli 4, Raimund Erbel 45, Karl-Heinz Jöckel 45, Susanne Moebus 45, Ulf de Faire 97, Anders Hamsten 47, Michael Stumvoll 99 100, Panagiotis Deloukas 32 103, Peter J Donnelly 5 104, Timothy M Frayling 78, Andrew T Hattersley 105, Samuli Ripatti 32 44 95 106, Veikko Salomaa 80, Nancy L Pedersen 107, Bernhard O Boehm 108 109, Richard N Bergman 110, Francis S Collins 79, Karen L Mohlke 111, Jaakko Tuomilehto 91 112 113 114, Torben Hansen 10 115, Oluf Pedersen 10, Inês Barroso 32 116, Lars Lannfelt 117, Erik Ingelsson 46 118, Lars Lind 119, Cecilia M Lindgren 5 94, Stephane Cauchi 40, Philippe Froguel 7 40 41, Ruth J F Loos 37 38 120, Beverley Balkau 121 122, Heiner Boeing 123, Paul W Franks 124 125, Aurelio Barricarte Gurrea 126 127 128, Domenico Palli 129, Yvonne T van der Schouw 130, David Altshuler 94 131 132 133 134 135, Leif C Groop 20 44, Claudia Langenberg 1, Nicholas J Wareham 1, Eric Sijbrands 90, Cornelia M van Duijn 33 136, Jose C Florez 8 132 137, James B Meigs 8 132 138, Eric Boerwinkle 139 140, Christian Gieger 24 25, Konstantin Strauch 27 29, Andres Metspalu 3 141, Andrew D Morris 142, Colin N A Palmer 17 143, Frank B Hu 14 15 16, Unnur Thorsteinsdottir 13 50, Kari Stefansson 13 50, Josée Dupuis 59 61, Andrew P Morris 3 5 144 145, Michael Boehnke 146, Mark I McCarthy 147 31 77, Inga Prokopenko 148 7 31; DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium

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Affiliations

1MRC Epidemiology Unit, University of Cambridge, Cambridge, U.K.
2Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI.
3Estonian Genome Center, University of Tartu, Tartu, Estonia.
4Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy.
5Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.
6Department of Genetics, Stanford University, Stanford, CA.
7Department of Genomics of Common Disease, Imperial College London, London, U.K.
8Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA.
9Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA.
10Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
11Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
12Framingham Heart Study, Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Framingham, MA.
13deCODE genetics, Amgen, Inc., Reykjavik, Iceland.
14Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA.
15Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA.
16Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
17Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics and Biomedical Research Institute, Ninewells Hospital, University of Dundee, Dundee, U.K.
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.
19Center for Precision Health, School Biomedical Informatics, and School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX.
20Lund University Diabetes Centre and Department of Clinical Sciences Malmö, University Hospital Scania, Lund University, Malmö, Sweden.
21Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
22Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
23Institute of Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
24Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
25Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
26German Center for Diabetes Research, Neuherberg, Germany.
27Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
28Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany.
29Genetic Epidemiology, Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
30Munich Heart Alliance, German Centre for Cardiovascular Disease, Munich, Germany.
31Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K.
32Wellcome Trust Sanger Institute, Hinxton, U.K.
33Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
34PolyOmica, 's-Hertogenbosch, the Netherlands.
35High Throughput Biology Center, Johns Hopkins University School of Medicine, Baltimore, MD.
36Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
37The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
38The Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, NY.
39l'institut du thorax, INSERM, CNRS, Centre Hospitalier Universitaire de Nantes, Université de Nantes, Nantes, France.
40Lille Institute of Biology, European Genomics Institute of Diabetes, Lille, France.
41CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, Lille, France.
42Leibniz Institute on Aging, Fritz Lipmann Institute, Jena, Germany.
43Institute of Medical Systems Biology, Ulm University, Ulm, Germany.
44Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
45Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, Essen, Germany.
46Molecular Epidemiology, Department of Medical Sciences, and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
47Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
48Science for Life Laboratory, Stockholm, Sweden.
49Department for Numerical Analysis and Computer Science, Stockholm University, Stockholm, Sweden.
50Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
51Landspítali University Hospital, Reykjavik, Iceland.
52Icelandic Heart Association, Kópavogur, Iceland.
53Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA.
54Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
55Institute of Human Genetics, Technische Universität München, Munich, Germany.
56Department of Endocrinology and Diabetology, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
57Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
58Division of Genetics and Endocrinology, Boston Children's Hospital, Boston, MA.
59Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, MA.
60Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
61Department of Biostatistics, Boston University School of Public Health, Boston, MA.
62Data Coordinating Center, Boston University School of Public Health, Boston, MA.
63Folkhälsan Research Center, Helsinki, Finland.
64Department of Social Services and Health Care, Jakobstad, Finland.
65Department of Medicine, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
66Collaborative Studies Coordinating Center, Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC.
67Division of Epidemiology & Community Health, University of Minnesota, Minneapolis, MN.
68Steno Diabetes Center, Gentofte, Denmark.
69Research Centre for Prevention and Health, Capital Region of Denmark, Copenhagen, Denmark.
70Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
71Faculty of Medicine, Aalborg University, Aalborg, Denmark.
72Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
73Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
74Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL.
75Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore.
76Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA.
77National Institute for Health Research Oxford Biomedical Research Centre, Churchill Hospital, Oxford, U.K.
78Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, U.K.
79National Human Genome Research Institute, National Institutes of Health, Bethesda, MD.
80Department of Health, National Institute for Health and Welfare, Helsinki, Finland.
81Endocrinology, Department of Medicine and Abdominal Center, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
82Minerva Foundation Institute for Medical Research, Biomedicum Helsinki 2U, Helsinki, Finland.
83Institute of Human Genetics, University of Bonn, Bonn, Germany.
84Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
85Centro Cardiologico Monzino, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy.
86Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Milan, Italy.
87Cardiovascular Genetics, BHF Laboratories, Institute Cardiovascular Sciences, University College London, London, U.K.
88Hannover Unified Biobank, Hannover Medical School, Hannover, Germany.
89Department of Clinical Chemistry and Central Laboratory, University of Ulm, Ulm, Germany.
90Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.
91Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
92Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland.
93Unit of General Practice, Helsinki University Central Hospital, Helsinki, Finland.
94Broad Institute of MIT and Harvard, Cambridge, MA.
95Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland.
96Endocrinology-Diabetology Unit, Corbeil-Essonnes Hospital, Corbeil-Essonnes, France.
97Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
98Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY.
99IFB AdiposityDiseases, University of Leipzig, Leipzig, Germany.
100Department of Medicine, University of Leipzig, Leipzig, Germany.

01 November 2017

doi: 10.2337/db16-1253

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

Affiliations

Abstract

References

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