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Diabetes. 2017 Nov;66(11):2888-2902. doi: 10.2337/db16-1253. Epub 2017 May 31.

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

Scott RA1, Scott LJ2, Mägi R3, Marullo L4, Gaulton KJ5,6, Kaakinen M7, Pervjakova N3, Pers TH8,9,10,11, Johnson AD12, Eicher JD12, Jackson AU2, Ferreira T5, Lee Y2, Ma C2, Steinthorsdottir V13, Thorleifsson G13, Qi L14,15,16, Van Zuydam NR5,17, Mahajan A5, Chen H18,19, Almgren P20, Voight BF21,22,23, Grallert H24,25,26, Müller-Nurasyid M27,28,29,30, Ried JS27, Rayner NW5,31,32, Robertson N5,31, Karssen LC33,34, van Leeuwen EM33, Willems SM1,33, Fuchsberger C2, Kwan P2, Teslovich TM2, Chanda P35, Li M36, Lu Y37,38, Dina C39, Thuillier D40,41, Yengo L40,41, Jiang L7, Sparso T10, Kestler HA42,43, Chheda H44, Eisele L45, Gustafsson S46, Frånberg M47,48,49, Strawbridge RJ47, Benediktsson R50,51, Hreidarsson AB51, Kong A13, Sigurðsson G51,52, Kerrison ND1, Luan J1, Liang L14,53, Meitinger T30,54,55, Roden M26,56,57, Thorand B25,26, Esko T3,8,58, Mihailov E3, Fox C59,60, Liu CT61, Rybin D62, Isomaa B63,64, Lyssenko V20, Tuomi T63,65, Couper DJ66, Pankow JS67, Grarup N10, Have CT10, Jørgensen ME68, Jørgensen T69,70,71, Linneberg A69,72,73, Cornelis MC74, van Dam RM15,75, Hunter DJ14,15,16,76, Kraft P14,53,76, Sun Q15,16, Edkins S32, Owen KR31,77, Perry JRB1, Wood AR78, Zeggini E32, Tajes-Fernandes J5, Abecasis GR2, Bonnycastle LL79, Chines PS79, Stringham HM2, Koistinen HA80,81,82, Kinnunen L80,81,82, Sennblad B47,48, Mühleisen TW83,84, Nöthen MM83,84, Pechlivanis S45, Baldassarre D85,86, Gertow K47, Humphries SE87, Tremoli E85,86, Klopp N24,88, Meyer J27, Steinbach G89, Wennauer R90, Eriksson JG63,91,92,93, Mӓnnistö S91, Peltonen L32,44,91,94, Tikkanen E44,95, Charpentier G96, Eury E41, Lobbens S41, Gigante B97, Leander K97, McLeod O47, Bottinger EP37, Gottesman O37, Ruderfer D98, Blüher M99,100, Kovacs P99,100, Tonjes A99,100, Maruthur NM36,101,102, Scapoli C4, Erbel R45, Jöckel KH45, Moebus S45, de Faire U97, Hamsten A47, Stumvoll M99,100, Deloukas P32,103, Donnelly PJ5,104, Frayling TM78, Hattersley AT105, Ripatti S32,44,95,106, Salomaa V80, Pedersen NL107, Boehm BO108,109, Bergman RN110, Collins FS79, Mohlke KL111, Tuomilehto J91,112,113,114, Hansen T10,115, Pedersen O10, Barroso I32,116, Lannfelt L117, Ingelsson E46,118, Lind L119, Lindgren CM5,94, Cauchi S40, Froguel P7,40,41, Loos RJF37,38,120, Balkau B121,122, Boeing H123, Franks PW124,125, Barricarte Gurrea A126,127,128, Palli D129, van der Schouw YT130, Altshuler D94,131,132,133,134,135, Groop LC20,44, Langenberg C1, Wareham NJ1, Sijbrands E90, van Duijn CM33,136, Florez JC8,132,137, Meigs JB8,132,138, Boerwinkle E139,140, Gieger C24,25, Strauch K27,29, Metspalu A3,141, Morris AD142, Palmer CNA17,143, Hu FB14,15,16, Thorsteinsdottir U13,50, Stefansson K13,50, Dupuis J59,61, Morris AP3,5,144,145, Boehnke M146, McCarthy MI147,31,77, Prokopenko I148,7,31; DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium.

Author information

1
MRC Epidemiology Unit, University of Cambridge, Cambridge, U.K.
2
Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI.
3
Estonian Genome Center, University of Tartu, Tartu, Estonia.
4
Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy.
5
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.
6
Department of Genetics, Stanford University, Stanford, CA.
7
Department of Genomics of Common Disease, Imperial College London, London, U.K.
8
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA.
9
Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA.
10
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
11
Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
12
Framingham Heart Study, Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Framingham, MA.
13
deCODE genetics, Amgen, Inc., Reykjavik, Iceland.
14
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA.
15
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA.
16
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
17
Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics and Biomedical Research Institute, Ninewells Hospital, University of Dundee, Dundee, U.K.
18
Human 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
Center for Precision Health, School Biomedical Informatics, and School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX.
20
Lund University Diabetes Centre and Department of Clinical Sciences Malmö, University Hospital Scania, Lund University, Malmö, Sweden.
21
Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
22
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
23
Institute of Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
24
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
25
Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
26
German Center for Diabetes Research, Neuherberg, Germany.
27
Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
28
Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany.
29
Genetic Epidemiology, Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
30
Munich Heart Alliance, German Centre for Cardiovascular Disease, Munich, Germany.
31
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K.
32
Wellcome Trust Sanger Institute, Hinxton, U.K.
33
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
34
PolyOmica, 's-Hertogenbosch, the Netherlands.
35
High Throughput Biology Center, Johns Hopkins University School of Medicine, Baltimore, MD.
36
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
37
The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
38
The Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, NY.
39
l'institut du thorax, INSERM, CNRS, Centre Hospitalier Universitaire de Nantes, Université de Nantes, Nantes, France.
40
Lille Institute of Biology, European Genomics Institute of Diabetes, Lille, France.
41
CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, Lille, France.
42
Leibniz Institute on Aging, Fritz Lipmann Institute, Jena, Germany.
43
Institute of Medical Systems Biology, Ulm University, Ulm, Germany.
44
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
45
Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, Essen, Germany.
46
Molecular Epidemiology, Department of Medical Sciences, and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
47
Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
48
Science for Life Laboratory, Stockholm, Sweden.
49
Department for Numerical Analysis and Computer Science, Stockholm University, Stockholm, Sweden.
50
Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
51
Landspítali University Hospital, Reykjavik, Iceland.
52
Icelandic Heart Association, Kópavogur, Iceland.
53
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA.
54
Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
55
Institute of Human Genetics, Technische Universität München, Munich, Germany.
56
Department of Endocrinology and Diabetology, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
57
Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
58
Division of Genetics and Endocrinology, Boston Children's Hospital, Boston, MA.
59
Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, MA.
60
Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
61
Department of Biostatistics, Boston University School of Public Health, Boston, MA.
62
Data Coordinating Center, Boston University School of Public Health, Boston, MA.
63
Folkhälsan Research Center, Helsinki, Finland.
64
Department of Social Services and Health Care, Jakobstad, Finland.
65
Department of Medicine, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
66
Collaborative Studies Coordinating Center, Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC.
67
Division of Epidemiology & Community Health, University of Minnesota, Minneapolis, MN.
68
Steno Diabetes Center, Gentofte, Denmark.
69
Research Centre for Prevention and Health, Capital Region of Denmark, Copenhagen, Denmark.
70
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
71
Faculty of Medicine, Aalborg University, Aalborg, Denmark.
72
Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
73
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
74
Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL.
75
Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore.
76
Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA.
77
National Institute for Health Research Oxford Biomedical Research Centre, Churchill Hospital, Oxford, U.K.
78
Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, U.K.
79
National Human Genome Research Institute, National Institutes of Health, Bethesda, MD.
80
Department of Health, National Institute for Health and Welfare, Helsinki, Finland.
81
Endocrinology, Department of Medicine and Abdominal Center, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
82
Minerva Foundation Institute for Medical Research, Biomedicum Helsinki 2U, Helsinki, Finland.
83
Institute of Human Genetics, University of Bonn, Bonn, Germany.
84
Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
85
Centro Cardiologico Monzino, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy.
86
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Milan, Italy.
87
Cardiovascular Genetics, BHF Laboratories, Institute Cardiovascular Sciences, University College London, London, U.K.
88
Hannover Unified Biobank, Hannover Medical School, Hannover, Germany.
89
Department of Clinical Chemistry and Central Laboratory, University of Ulm, Ulm, Germany.
90
Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.
91
Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
92
Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland.
93
Unit of General Practice, Helsinki University Central Hospital, Helsinki, Finland.
94
Broad Institute of MIT and Harvard, Cambridge, MA.
95
Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland.
96
Endocrinology-Diabetology Unit, Corbeil-Essonnes Hospital, Corbeil-Essonnes, France.
97
Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
98
Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY.
99
IFB AdiposityDiseases, University of Leipzig, Leipzig, Germany.
100
Department of Medicine, University of Leipzig, Leipzig, Germany.
101
Division of General Internal Medicine, Department of Medicine, Johns Hopkins Bloomberg School of Medicine, Baltimore, MD.
102
The Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins University, Baltimore, MD.
103
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University London, London, U.K.
104
Department of Statistics, University of Oxford, Oxford, U.K.
105
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K.
106
Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland.
107
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
108
Division of Endocrinology and Diabetes, Department of Internal Medicine, University Medical Centre Ulm, Ulm, Germany.
109
Lee Kong Chian School of Medicine, Imperial College London and Nanyang Technological University, Singapore, Singapore.
110
Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA.
111
Department of Genetics, University of North Carolina, Chapel Hill, NC.
112
Dasman Diabetes Institute, Dasman, Kuwait.
113
Centre for Vascular Prevention, Danube University Krems, Krems, Austria.
114
Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia.
115
Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
116
University 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
Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.
118
Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA.
119
Cardiovascular Epidemiology, Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden.
120
The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
121
INSERM, CESP, UMR 1018, Villejuif, France.
122
University of Paris-Sud, UMR 1018, Villejuif, France.
123
German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.
124
Lund University, Malmö, Sweden.
125
Umeå University, Umeå, Sweden.
126
Navarra Public Health Institute, Pamplona, Spain.
127
Navarra Institute for Health Research, Pamplona, Spain.
128
CIBER Epidemiology and Public Health, Madrid, Spain.
129
Cancer Research and Prevention Institute, Florence, Italy.
130
University Medical Center Utrecht, Utrecht, the Netherlands.
131
Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA.
132
Department of Medicine, Harvard Medical School, Boston, MA.
133
Department of Genetics, Harvard Medical School, Boston, MA.
134
Department of Molecular Biology, Harvard Medical School, Boston, MA.
135
Diabetes Unit, Massachusetts General Hospital, Boston, MA.
136
Netherlands Genomics Initiative, Netherlands Consortium for Healthy Ageing and Center for Medical Systems Biology, Rotterdam, the Netherlands.
137
Diabetes Unit and Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA.
138
General Medicine Division, Massachusetts General Hospital, Boston, MA.
139
Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, TX.
140
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX.
141
Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
142
Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, Edinburgh, U.K.
143
Cardiovascular and Diabetes Medicine, Biomedical Research Institute, Ninewells Hospital, University of Dundee, Dundee, U.K.
144
Department of Biostatistics, University of Liverpool, Liverpool, U.K.
145
Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, U.K.
146
Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI boehnke@umich.edu.
147
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K. mark.mccarthy@drl.ox.ac.uk.
148
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K. i.prokopenko@imperial.ac.uk.

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.

Comment in

PMID:
28566273
PMCID:
PMC5652602
DOI:
10.2337/db16-1253
[Indexed for MEDLINE]
Free PMC Article

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