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Nature. 2016 Aug 4;536(7614):41-47. doi: 10.1038/nature18642. Epub 2016 Jul 11.

The genetic architecture of type 2 diabetes.

Fuchsberger C#1,2,3, Flannick J#4,5, Teslovich TM#1, Mahajan A#6, Agarwala V#4,7, Gaulton KJ#6, Ma C1, Fontanillas P4, Moutsianas L6, McCarthy DJ6,8, Rivas MA6, Perry JRB6,9,10,11, Sim X1, Blackwell TW1, Robertson NR6,12, Rayner NW6,12,13, Cingolani P14,15, Locke AE1, Tajes JF6, Highland HM16, Dupuis J17,18, Chines PS19, Lindgren CM4,6, Hartl C4, Jackson AU1, Chen H17,20, Huyghe JR1, van de Bunt M6,12, Pearson RD6, Kumar A6,21, Müller-Nurasyid M22,23,24,25, Grarup N26, Stringham HM1, Gamazon ER27, Lee J28, Chen Y6, Scott RA10, Below JE29, Chen P30, Huang J31, Go MJ32, Stitzel ML33, Pasko D9, Parker SCJ34, Varga TV35, Green T4, Beer NL12, Day-Williams AG13, Ferreira T6, Fingerlin T36, Horikoshi M6,12, Hu C37, Huh I28, Ikram MK38,39,40, Kim BJ32, Kim Y28, Kim YJ32, Kwon MS41, Lee J32, Lee S28, Lin KH1, Maxwell TJ29, Nagai Y15,42,43, Wang X30, Welch RP1, Yoon J41, Zhang W44,45, Barzilai N46, Voight BF47,48, Han BG32, Jenkinson CP49,50, Kuulasmaa T51, Kuusisto J51,52, Manning A4, Ng MCY53,54, Palmer ND53,54,55, Balkau B56, Stančáková A51, Abboud HE49, Boeing H57, Giedraitis V58, Prabhakaran D59, Gottesman O60, Scott J61, Carey J4, Kwan P1, Grant G4, Smith JD62, Neale BM4,63,64, Purcell S4,64,65, Butterworth AS66, Howson JMM66, Lee HM67, Lu Y60, Kwak SH68, Zhao W69, Danesh J13,66,70, Lam VKL67, Park KS68,71, Saleheen D72,73, So WY67, Tam CHT67, Afzal U44, Aguilar D74, Arya R75, Aung T38,39,40, Chan E76, Navarro C77,78,79, Cheng CY30,38,39,40, Palli D80, Correa A81, Curran JE82, Rybin D17, Farook VS83, Fowler SP49, Freedman BI84, Griswold M85, Hale DE75, Hicks PJ53,54,55, Khor CC30,38,39,86,87, Kumar S82, Lehne B44, Thuillier D88, Lim WY30, Liu J30,87, van der Schouw YT89, Loh M44,90,91, Musani SK92, Puppala S83, Scott WR44, Yengo L88, Tan ST45,61, Taylor HA Jr81, Thameem F49, Wilson G Sr93, Wong TY38,39,40, Njølstad PR94,95, Levy JC12, Mangino M11, Bonnycastle LL19, Schwarzmayr T96, Fadista J97, Surdulescu GL11, Herder C98,99, Groves CJ12, Wieland T96, Bork-Jensen J26, Brandslund I100,101, Christensen C102, Koistinen HA103,104,105,106, Doney ASF107, Kinnunen L103, Esko T4,108,109,110, Farmer AJ111, Hakaste L104,112,113, Hodgkiss D11, Kravic J97, Lyssenko V97, Hollensted M26, Jørgensen ME114, Jørgensen T115,116,117, Ladenvall C97, Justesen JM26, Käräjämäki A118,119, Kriebel J99,120,121, Rathmann W122, Lannfelt L58, Lauritzen T123, Narisu N19, Linneberg A115,124,125, Melander O126, Milani L108, Neville M12,127, Orho-Melander M128, Qi L129,130, Qi Q129,131, Roden M98,99,132, Rolandsson O133, Swift A19, Rosengren AH97, Stirrups K13, Wood AR9, Mihailov E108, Blancher C134, Carneiro MO4, Maguire J4, Poplin R4, Shakir K4, Fennell T4, DePristo M4, de Angelis MH99,135,136, Deloukas P137,138, Gjesing AP26, Jun G1,29, Nilsson P139, Murphy J4, Onofrio R4, Thorand B99,120, Hansen T26,140, Meisinger C99,120, Hu FB31,129, Isomaa B112,141, Karpe F12,127, Liang L20,31, Peters A25,99,120, Huth C99,120, O'Rahilly SP142, Palmer CNA143, Pedersen O26, Rauramaa R144, Tuomilehto J103,145,146,147,148, Salomaa V148, Watanabe RM149,150,151, Syvänen AC152, Bergman RN153, Bharadwaj D154, Bottinger EP60, Cho YS155, Chandak GR156, Chan JCN67,157,158, Chia KS30, Daly MJ63, Ebrahim SB59, Langenberg C10, Elliott P44,159, Jablonski KA160, Lehman DM49, Jia W37, Ma RCW67,157,158, Pollin TI161, Sandhu M13,66, Tandon N162, Froguel P88,163, Barroso I13,142, Teo YY30,164,165, Zeggini E13, Loos RJF60, Small KS11, Ried JS22, DeFronzo RA49, Grallert H99,120,121, Glaser B166, Metspalu A108, Wareham NJ10, Walker M167, Banks E4, Gieger C22,120,121, Ingelsson E6,168, Im HK27, Illig T121,169,170, Franks PW35,129,133, Buck G134, Trakalo J134, Buck D134, Prokopenko I6,12,163, Mägi R108, Lind L171, Farjoun Y172, Owen KR12,127, Gloyn AL6,12,127, Strauch K22,24, Tuomi T104,112,113,173, Kooner JS45,61,174, Lee JY32, Park T28,41, Donnelly P6,8, Morris AD175,176, Hattersley AT177, Bowden DW53,54,55, Collins FS19, Atzmon G46,178, Chambers JC44,45,174, Spector TD11, Laakso M51,52, Strom TM96,179, Bell GI180, Blangero J82, Duggirala R83, Tai ES30,76,181, McVean G6,182, Hanis CL29, Wilson JG183, Seielstad M184,185, Frayling TM9, Meigs JB186, Cox NJ27, Sladek R15,42,187, Lander ES188, Gabriel S4, Burtt NP4, Mohlke KL189, Meitinger T96,179, Groop L97,173, Abecasis G1, Florez JC4,64,190,191, Scott LJ1, Morris AP6,108,192, Kang HM1, Boehnke M1, Altshuler D4,5,109,190,191,193, McCarthy MI6,12,127.

Author information

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, ASTAR, 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 (ASTAR), 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.
#
Contributed equally

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 the heritability of this disease. Here, 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 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the 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 the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.

PMID:
27398621
PMCID:
PMC5034897
DOI:
10.1038/nature18642
[Indexed for MEDLINE]
Free PMC Article

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