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Nat Genet. 2015 Dec;47(12):1415-25. doi: 10.1038/ng.3437. Epub 2015 Nov 9.

Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.

Gaulton KJ1,2, Ferreira T1, Lee Y3, Raimondo A4, Mägi R5, Reschen ME6, Mahajan A1, Locke A3, Rayner NW1,4,7, Robertson N1,4, Scott RA8, Prokopenko I9, Scott LJ3, Green T10, Sparso T11, Thuillier D12, Yengo L12, Grallert H13,14,15, Wahl S13,14,15, Frånberg M16,17,18, Strawbridge RJ16, Kestler H19,20, Chheda H21, Eisele L22, Gustafsson S23, Steinthorsdottir V24, Thorleifsson G24, Qi L25,26,27,28, Karssen LC29, van Leeuwen EM29, Willems SM8,29, Li M30, Chen H31,32, Fuchsberger C3, Kwan P3, Ma C3, Linderman M33, Lu Y34, Thomsen SK4, Rundle JK4, Beer NL1,4, van de Bunt M1,4, Chalisey A6, Kang HM3, Voight BF35, Abecasis GR3, Almgren P36, Baldassarre D37,38, Balkau B39,40, Benediktsson R41,42, Blüher M43,44, Boeing H45, Bonnycastle LL46, Bottinger EP47, Burtt NP10, Carey J10, Charpentier G48, Chines PS46, Cornelis MC49, Couper DJ50, Crenshaw AT10, van Dam RM26,51, Doney AS52,53, Dorkhan M54, Edkins S7, Eriksson JG55,56,57,58, Esko T5,59,60, Eury E61, Fadista J36, Flannick J10, Fontanillas P10, Fox C62,63, Franks PW26,36,64,65, Gertow K16, Gieger C13,14, Gigante B66, Gottesman O47, Grant GB10, Grarup N11, Groves CJ4, Hassinen M67, Have CT11, Herder C68,69, Holmen OL70, Hreidarsson AB42, Humphries SE71, Hunter DJ25,26,27,72, Jackson AU3, Jonsson A36, Jørgensen ME73, Jørgensen T74,75,76, Kao WH30, Kerrison ND8, Kinnunen L55, Klopp N13,77, Kong A24, Kovacs P43,44, Kraft P25,32,72, Kravic J36, Langford C7, Leander K66, Liang L25,32, Lichtner P78, Lindgren CM1,10, Lindholm E36, Linneberg A74,79,80, Liu CT31, Lobbens S61, Luan J8, Lyssenko V36,73, Männistö S55, McLeod O16, Meyer J81, Mihailov E5, Mirza G82, Mühleisen TW83,84,85, Müller-Nurasyid M81,86,87,88, Navarro C89,90,91, Nöthen MM83,84, Oskolkov NN36, Owen KR4,92, Palli D93, Pechlivanis S22, Peltonen L7,10,21,55, Perry JR8, Platou CG70,94, Roden M68,69,95, Ruderfer D96, Rybin D97, van der Schouw YT98, Sennblad B16,17, Sigurðsson G42,99, Stančáková A100, Steinbach G101, Storm P36, Strauch K81,87, Stringham HM3, Sun Q26,27, Thorand B14,15, Tikkanen E21,102, Tonjes A43,44, Trakalo J1, Tremoli E37,38, Tuomi T21,58,103,104, Wennauer R105, Wiltshire S1, Wood AR106, Zeggini E7, Dunham I107, Birney E107, Pasquali L108,109,110, Ferrer J111,112, Loos RJ8,34,47,113, Dupuis J31,62, Florez JC60,114,115,116, Boerwinkle E117,118, Pankow JS119, van Duijn C29,120, Sijbrands E105, Meigs JB114,121, Hu FB25,26,27, Thorsteinsdottir U24,41, Stefansson K24,41, Lakka TA67,122,123, Rauramaa R67,123, Stumvoll M43,44, Pedersen NL124, Lind L125, Keinanen-Kiukaanniemi SM126,127, Korpi-Hyövälti E128, Saaristo TE129,130, Saltevo J131, Kuusisto J100, Laakso M100, Metspalu A5,132, Erbel R133, Jöcke KH122, Moebus S22, Ripatti S7,21,102,134, Salomaa V55, Ingelsson E1,23, Boehm BO135,136, Bergman RN137, Collins FS46, Mohlke KL138, Koistinen H55,139,140, Tuomilehto J55,141,142,143, Hveem K70, Njølstad I144, Deloukas P7,145, Donnelly PJ1,146, Frayling TM106, Hattersley AT147, de Faire U66, Hamsten A16, Illig T13,77, Peters A14,15,88, Cauchi S12, Sladek R148,149, Froguel P9,12,61, Hansen T11,150, Pedersen O11, Morris AD151, Palmer CN52,53, Kathiresan S10,115,152, Melander O36, Nilsson PM36, Groop LC21,36, Barroso I7,153,154, Langenberg C8, Wareham NJ8, O'Callaghan CA6, Gloyn AL1,4,92, Altshuler D10,114,115,116,155,156, Boehnke M3, Teslovich TM3, McCarthy MI1,4,92, Morris AP1,5,157,158; DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium.

Collaborators (266)

Abecasis GR, Almgren P, Atalay M, Baldassarre D, Balkau B, Barroso I, Beer NL, Beilby J, Benediktsson R, Bergman RN, Birney E, Blüher M, Boehm BO, Boeing H, Boerwinkle E, Bonnycastle LL, Borringer EP, van de Bunt M, Burtt NP, Campbell H, Carey J, Cauchi S, Charpentier G, Chen H, Chheda H, Chines PS, Collins FS, Cornelis MC, Couper DJ, Crenshaw AT, van Dam RM, Danesh J, de Faire U, Dedoussis G, Deloukas P, Dimas AS, Dina C, Doney AS, Donnelly PJ, Dorkhan M, van Duijn C, Dunham I, Dupuis J, Edkins S, Eisele L, Emilsson V, Erbel R, Eriksson JG, Esko T, Eury E, Fadista J, Ferreira T, Ferrer J, Flannick J, Florez JC, Fontanillas P, Forouhi NG, Fox C, Frånberg M, Franks PW, Frayling TM, Froguel P, Fuchsberger C, Gaulton KJ, Gertow K, Gieger C, Gigante B, Gloyn AL, Gottesman O, Grallert H, Grant GB, Grarup N, Green T, Groop LC, Groves CJ, Gustafsson S, Hamsten A, Hansen T, Hassinen M, Hattersley AT, Have CT, Hayward C, Herder C, Hofman A, Holmen OL, Horikoshi M, Hovingh K, Hreidarsson AB, Hu FB, Hui J, Humphries SE, Hunt SE, Hunter DJ, Hveem K, Illig T, Ingelsson E, Jackson AU, James A, Jockel KH, Johnson AD, Jonsson A, Jørgensen ME, Jørgensen T, Kang HM, Kanoni S, Kao WH, Karssen LC, Kathiresan S, Keinanen-Kiukaanniemi SM, Kerrison ND, Kestler H, Khan H, Khaw KT, Kinnunen L, Klopp N, Koistinen H, Komulainen P, Kong A, Korpi-Hyövӓlti E, Kovacs P, Kraft P, Kravic J, Kumar A, Kuusisto J, Kwan P, Laakso M, Lagou V, Lakka TA, Langenberg C, Langford C, Leander K, Lee Y, van Leeuwen EM, Li M, Liang L, Lichtner P, Lind L, Linderman M, Lindgren CM, Lindholm E, Linneberg A, Liu CT, Lobbens S, Locke A, Loos RJ, Lu Y, Luan J, Lyssenko V, Ma C, Mägi R, Mahajan A, McLeod O, Meigs JB, Melander O, Metspalu A, Meyer J, Mihailov E, Mirza G, Moebus S, Mohlke KL, Morris AD, Morris AP, Mühleisen TW, Müller-Nurasyid M, Musk B, Mӓnnistö S, Navarro C, Navarro P, Nilsson PM, Njølstad I, Nöthen MM, O'Callaghan CA, Oskolkov NN, Owen KR, Palli D, Palmer CN, Pankow JS, Pasquali L, Pechlivanis S, Pedersen NL, Pedersen O, Peltonen L, Perry JR, Peters A, Platou CG, Potter S, Price JF, Prokopenko I, Qi L, Raimondo A, Rallidis L, Rathmann W, Rauramaa R, Raychaudhuri S, Rayner NW, Rehnberg E, Reschen ME, Ripatti S, Robertson N, Roden M, Rossin EJ, Rudan I, Ruderfer D, Rundle JK, Rybin D, Saaristo TE, Salehen D, Salomaa V, Saltevo J, Saramies J, van der Schouw YT, Scott LJ, Scott RA, Segre AV, Sennblad B, Shah S, Shuldiner AR, Sigurðsson G, Sijbrands E, Silveira A, Sivapalaratnam S, Sladek R, Sparso T, Stančáková A, Stefansson K, Steinbach G, Steinthorsdottir V, Stirrups K, Storm P, Strauch K, Strawbridge RJ, Stringham HM, Stumvoll M, Sun Q, Syvanen AC, Teslovich TM, Thomsen SK, Thorand B, Thorleifsson G, Thorsteinsdottir U, Thuillier D, Tikkanen E, Tonjes A, Trakalo J, Tremoli E, Trip MD, Tuomi T, Tuomilehto J, Uitterlinden AG, Vedantam S, Veglia F, Voight BF, Wahl S, Wareham NJ, Wennauer R, Willems SM, Wilsgaard T, Wilson JF, Wiltshire S, Wood AR, Yengo L, Zabaneh D, Zeggini E, Altshuler D, Boehnke M, McCarthy MI.

Author information

1
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
2
Department of Genetics, Stanford University, Stanford, California, USA.
3
Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.
4
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.
5
Estonian Genome Center, University of Tartu, Tartu, Estonia.
6
Centre for Cellular and Molecular Physiology, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
7
Wellcome Trust Sanger Institute, Hinxton, UK.
8
Medical Research Council (MRC) Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, UK.
9
Genomics of Common Disease, Imperial College London, London, UK.
10
Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
11
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
12
Lille Institute of Biology, European Genomics Institute of Diabetes, Lille, France.
13
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
14
Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
15
German Center for Diabetes Research, Neuherberg, Germany.
16
Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
17
Science for Life Laboratory, Stockholm, Sweden.
18
Department for Numerical Analysis and Computer Science, Stockholm University, Stockholm, Sweden.
19
Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany.
20
Medical Systems Biology, Ulm University, Ulm, Germany.
21
Finnish Institute for Molecular Medicine (FIMM), Helsinki, Finland.
22
Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, Essen, Germany.
23
Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
24
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
25
Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.
26
Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.
27
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
28
Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane University, New Orleans, Louisiana, USA.
29
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
30
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
31
Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.
32
Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA.
33
Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
34
Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
35
Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
36
Lund University Diabetes Centre, Department of Clinical Science Malmo, Scania University Hospital, Lund University, Malmo, Sweden.
37
Centro Cardiologico Monzino, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy.
38
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Milan, Italy.
39
INSERM Centre de Recherche Epidémiologie et Santé des Populations (CESP) U1018, Villejuif, France.
40
University Paris Sud 11, UMRS 1018, Villejuif, France.
41
Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
42
Landspitali University Hospital, Reykjavik, Iceland.
43
Integrated Treatment and Research (IFB) Center for Adiposity Diseases, University of Leipzig, Leipzig, Germany.
44
Department of Medicine, University of Leipzig, Leipzig, Germany.
45
German Institute of Human Nutrition, Potsdam-Rehbruecke, Germany.
46
National Human Genome Research Institute, US National Institutes of Health, Bethesda, Maryland, USA.
47
Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
48
Endocrinology-Diabetology Unit, Corbeil-Essonnes Hospital, Corbeil-Essonnes, France.
49
Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
50
Collaborative Studies Coordinating Center, Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
51
Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
52
Diabetes Research Centre, Biomedical Research Institute, University of Dundee, Ninewells Hospital, Dundee, UK.
53
Pharmacogenomics Centre, Biomedical Research Institute, University of Dundee, Ninewells Hospital, Dundee, UK.
54
Lund University Diabetes Centre, Department of Clinical Science Malmo, Novo Nordisk Scandinavia, Malmo, Sweden.
55
Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
56
Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland.
57
Unit of General Practice, Helsinki University General Hospital, Helsinki, Finland.
58
Folkhalsan Research Center, Helsinki, Finland.
59
Division of Endocrinology, Children's Hospital, Boston, Massachusetts, USA.
60
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
61
CNRS UMR 8199, Institute of Biology and Lille 2 University, Pasteur Institute, Lille, France.
62
National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA.
63
Division of Endocrinology and Metabolism, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
64
Department of Clinical Sciences, Lund University, Malmo, Sweden.
65
Department of Public Health and Clinical Medicine, Umea University, Umea, Sweden.
66
Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
67
Kuopio Research Institute of Exercise Medicine, Kuopio, Finland.
68
Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Dusseldorf, Dusseldorf, Germany.
69
German Center for Diabetes Research, partner site Dusseldorf, Dusseldorf, Germany.
70
Nord-Trøndelag Health Study (HUNT) Research Center, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Norway.
71
Cardiovascular Genetics, British Heart Foundation (BHF) Laboratories, Institute of Cardiovascular Sciences, University College London, London, UK.
72
Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, Massachusetts, USA.
73
Steno Diabetes Center, Gentofte, Denmark.
74
Research Centre for Prevention and Health, Capital Region of Denmark, Copenhagen, Denmark.
75
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
76
Faculty of Medicine, University of Aalborg, Aalborg, Denmark.
77
Hannover Unified Biobank, Hannover Medical School, Hannover, Germany.
78
Institute of Human Genetics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
79
Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
80
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
81
Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
82
Biomedical Research Centre Genomics Core Facility, Guy's and St Thomas' National Health Service (NHS) Foundation Trust, Guy's &St Thomas' Hospital, London, UK.
83
Institute of Human Genetics, University of Bonn, Bonn, Germany.
84
Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
85
Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, Jülich, Germany.
86
Department of Medicine I, University Hospital Grosshadern, Ludwig Maximilians Universität, Munich, Germany.
87
Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig Maximilians Universität, Neuherberg, Germany.
88
DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
89
Department of Epidemiology, Murcia Regional Health Council, Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain.
90
Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
91
Department of Health and Social Sciences, Universidad de Murcia, Murcia, Spain.
92
Oxford National Institute for Health Research Biomedical Research Centre, Churchill Hospital, Oxford, UK.
93
Cancer Research and Prevention Institute (ISPO), Florence, Italy.
94
Department of Internal Medicine, Levanger Hospital, Nord-Trondelag Health Trust, Levanger, Norway.
95
Department of Endocrinology and Diabetology, University Hospital Dusseldorf, Dusseldorf, Germany.
96
Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
97
Boston University Data Coordinating Center, Boston, Massachusetts, USA.
98
University Medical Center Utrecht, Utrecht, the Netherlands.
99
Icelandic Heart Association, Kopavogur, Iceland.
100
Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
101
Department of Clinical Chemistry and Central Laboratory, University of Ulm, Ulm, Germany.
102
Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland.
103
Department of Endocrinology, Abdominal Center, Helsinki University Hospital, Helsinki, Finland.
104
Research Program for Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
105
Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.
106
Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.
107
European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton, UK.
108
Division of Endocrinology, Germans Trias i Pujol University Hospital and Research Institute, Badalona, Spain.
109
Josep Carreras Leukaemia Research Institute, Badalona, Spain.
110
CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain.
111
Department of Medicine, Imperial College London, London, UK.
112
Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centre Esther Koplowitz, Barcelona, Spain.
113
Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
114
Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
115
Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
116
Diabetes Research Center, Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
117
Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas, USA.
118
Human Genome Sequencing Center at Baylor College of Medicine, Houston, Texas, USA.
119
Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota, USA.
120
Netherlands Genomics Initiative, Netherlands Consortium for Healthy Ageing and Center for Medical Systems Biology, Rotterdam, the Netherlands.
121
General Medicine Division, Massachusetts General Hospital, Boston, Massachusetts, USA.
122
Institute of Biomedicine/Physiology, University of Eastern Finland, Kuopio, Finland.
123
Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland.
124
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
125
Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden.
126
Faculty of Medicine, Institute of Health Sciences, University of Oulu, Oulu, Finland.
127
Unit of General Practice, Oulu University Hospital, Oulu, Finland.
128
South Ostrobothnia Central Hospital, Seinajoki, Finland.
129
Finnish Diabetes Association, Tampere, Finland.
130
Pirkanmaa District Hospital, Tampere, Finland.
131
Department of Medicine, Central Finland Central Hospital, Jyvasklya, Finland.
132
Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
133
Clinic of Cardiology, West German Heart Centre, University Hospital of Essen, University Duisdurg-Essen, Essen, Germany.
134
Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland.
135
Division of Endocrinology and Diabetes, Department of Internal Medicine, University Medical Centre Ulm, Ulm, Germany.
136
Lee Kong Chian School of Medicine, Imperial College London and Nanyang Technological University, Singapore.
137
Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
138
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
139
Division of Endocrinology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland.
140
Minerva Foundation Institute for Medical Research, Helsinki, Finland.
141
Instituto de Investigación Sanitaria del Hospital Universitario La Paz, Madrid, Spain.
142
Centre for Vascular Prevention, Danube University Krems, Krems, Austria.
143
Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia.
144
Department of Community Medicine, Faculty of Health Sciences, University of Tromso, Tromso, Norway.
145
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
146
Department of Statistics, University of Oxford, Oxford, UK.
147
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
148
Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada.
149
McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada.
150
Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
151
Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
152
Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA.
153
University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK.
154
National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK.
155
Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
156
Department of Molecular Biology, Harvard Medical School, Boston, Massachusetts, USA.
157
Department of Biostatistics, University of Liverpool, Liverpool, UK.
158
Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.

Abstract

We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.

Comment in

PMID:
26551672
PMCID:
PMC4666734
DOI:
10.1038/ng.3437
[Indexed for MEDLINE]
Free PMC Article

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