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Nature. 2019 Jun;570(7759):71-76. doi: 10.1038/s41586-019-1231-2. Epub 2019 May 22.

Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls.

Flannick J1,2,3,4, Mercader JM5,6,7,8,9, Fuchsberger C10,11,12, Udler MS5,6,7,8,9, Mahajan A13,14, Wessel J15,16,17, Teslovich TM18, Caulkins L5,6, Koesterer R5,6, Barajas-Olmos F19, Blackwell TW10,12, Boerwinkle E20,21, Brody JA22, Centeno-Cruz F19, Chen L8,9, Chen S10,12, Contreras-Cubas C19, Córdova E19, Correa A23, Cortes M24, DeFronzo RA25, Dolan L26, Drews KL27, Elliott A5,6,8,9, Floyd JS28, Gabriel S24, Garay-Sevilla ME29,30, García-Ortiz H19, Gross M31, Han S32, Heard-Costa NL33,34, Jackson AU10,12, Jørgensen ME35,36,37, Kang HM10,12, Kelsey M27, Kim BJ32, Koistinen HA38,39,40, Kuusisto J41,42, Leader JB43, Linneberg A44,45,46, Liu CT47, Liu J48,49,50, Lyssenko V51,52, Manning AK9,53, Marcketta A18, Malacara-Hernandez JM29,30, Martínez-Hernández A19, Matsuo K10,12, Mayer-Davis E54, Mendoza-Caamal E19, Mohlke KL55, Morrison AC20, Ndungu A13, Ng MCY56,57,58, O'Dushlaine C18, Payne AJ13, Pihoker C59; Broad Genomics Platform, Post WS60, Preuss M61, Psaty BM62,63,64,65,66, Vasan RS34,67, Rayner NW13,14,68, Reiner AP65, Revilla-Monsalve C69, Robertson NR13,14, Santoro N70, Schurmann C61, So WY71,72,73, Soberón X19, Stringham HM10,12, Strom TM74,75, Tam CHT71,72,73, Thameem F76, Tomlinson B71, Torres JM13, Tracy RP77,78, van Dam RM49,50,79, Vujkovic M80, Wang S47, Welch RP10,12, Witte DR81,82, Wong TY83,84,85, Atzmon G86,87,88, Barzilai N86,88, Blangero J89,90, Bonnycastle LL91, Bowden DW56,57,58, Chambers JC92,93,94, Chan E49, Cheng CY95, Cho YS96, Collins FS91, de Vries PS20, Duggirala R89,90, Glaser B97, Gonzalez C98, Gonzalez ME99, Groop L51,100, Kooner JS101, Kwak SH102, Laakso M41,42, Lehman DM25, Nilsson P103, Spector TD104, Tai ES49,50,84, Tuomi T100,105,106,107, Tuomilehto J108,109,110,111, Wilson JG112, Aguilar-Salinas CA113, Bottinger E61, Burke B27, Carey DJ43, Chan JCN71,72,73, Dupuis J34,47, Frossard P114, Heckbert SR62,65, Hwang MY32, Kim YJ32, Kirchner HL43, Lee JY115, Lee J32, Loos RJF61,116, Ma RCW71,72,73, Morris AD117, O'Donnell CJ118,119,120,121, Palmer CNA122, Pankow J123, Park KS101,124,125, Rasheed A114, Saleheen D80,114, Sim X50, Small KS104, Teo YY50,126,127, Haiman C128, Hanis CL129, Henderson BE128, Orozco L19, Tusié-Luna T113,130, Dewey FE18, Baras A18, Gieger C131,132, Meitinger T74,75,133, Strauch K131,134, Lange L135, Grarup N136, Hansen T136,137, Pedersen O136, Zeitler P138, Dabelea D139, Abecasis G10,12, Bell GI29,30, Cox NJ140, Seielstad M141,142, Sladek R143,144,145, Meigs JB24,9,146, Rich SS147, Rotter JI148,149,150; DiscovEHR Collaboration; CHARGE; LuCamp; ProDiGY; GoT2D; ESP; SIGMA-T2D; T2D-GENES; AMP-T2D-GENES, Altshuler D5,6,8,9,151,152,153, Burtt NP5,6, Scott LJ10,12, Morris AP13,154, Florez JC5,6,7,8,9, McCarthy MI13,14,155, Boehnke M10,12.

Author information

1
Program in Metabolism, Broad Institute, Cambridge, MA, USA. flannick@broadinstitute.org.
2
Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA. flannick@broadinstitute.org.
3
Department of Pediatrics, Harvard Medical School, Boston, MA, USA. flannick@broadinstitute.org.
4
Program in Medical & Population Genetics, Broad Institute, Cambridge, MA, USA. flannick@broadinstitute.org.
5
Program in Metabolism, Broad Institute, Cambridge, MA, USA.
6
Program in Medical & Population Genetics, Broad Institute, Cambridge, MA, USA.
7
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
8
Diabetes Research Center (Diabetes Unit), Massachusetts General Hospital, Boston, MA, USA.
9
Department of Medicine, Harvard Medical School, Boston, MA, USA.
10
Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
11
Institute for Biomedicine, Eurac Research, Bolzano, Italy.
12
Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
13
Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
14
Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
15
Department of Epidemiology, Fairbanks School of Public Health, Indiana University, Indianapolis, IN, USA.
16
Department of Medicine, School of Medicine, Indiana University, Indianapolis, IN, USA.
17
Diabetes Translational Research Center, Indiana University, Indianapolis, IN, USA.
18
Regeneron Genetics Center, Regeneron Pharmaceuticals, Tarrytown, NY, USA.
19
Instituto Nacional de Medicina Genómica, Mexico City, Mexico.
20
Human Genetics Center, Department of Epidemiology Human Genetics and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
21
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
22
Cardiovascular Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
23
Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
24
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
25
Department of Medicine, University of Texas Health Science Center, San Antonio, TX, USA.
26
Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
27
Biostatistics Center, George Washington University, Rockville, MD, USA.
28
Department of Medicine and Epidemiology, University of Washington, Seattle, WA, USA.
29
Department of Medicine, The University of Chicago, Chicago, IL, USA.
30
Department of Human Genetics, The University of Chicago, Chicago, IL, USA.
31
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
32
Division of Genome Research, Center for Genome Science, National Institute of Health, Chungcheongbuk-do, South Korea.
33
Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
34
National Heart Lung and Blood Institute's Framingham Heart Study, Framingham, MA, USA.
35
Steno Diabetes Center Copenhagen, Gentofte, Denmark.
36
National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark.
37
Greenland Centre for Health Research, University of Greenland, Nuuk, Greenland.
38
Department of Public Health Solutions, National Institute for Health and Welfare, Helsinki, Finland.
39
University of Helsinki and Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland.
40
Minerva Foundation Institute for Medical Research, Helsinki, Finland.
41
Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland.
42
Department of Medicin, Kuopio University Hospital, Kuopio, Finland.
43
Geisinger Health System, Danville, PA, USA.
44
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
45
Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark.
46
Department of Clinical Experimental Research, Rigshospitalet, Copenhagen, Denmark.
47
Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
48
Genome Institute of Singapore, Agency for Science Technology and Research, Singapore, Singapore.
49
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore, Singapore.
50
Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore.
51
Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Malmö, Sweden.
52
Department of Clinical Science, University of Bergen, Bergen, Norway.
53
Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Harvard University, Boston, MA, USA.
54
University of North Carolina Chapel Hill, Chapel Hill, NC, USA.
55
Department of Genetics, University of North Carolina Chapel Hill, Chapel Hill, NC, USA.
56
Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC, USA.
57
Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, USA.
58
Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
59
Seattle Children's Hospital, Seattle, WA, USA.
60
Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
61
Charles R. Bronfman Institute of Personalized Medicine, Mount Sinai School of Medicine, New York, NY, USA.
62
Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA.
63
Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
64
Department of Medicine, University of Washington, Seattle, WA, USA.
65
Department of Epidemiology, University of Washington, Seattle, WA, USA.
66
Department of Health Services, University of Washington, Seattle, WA, USA.
67
Preventive Medicine & Epidemiology, Medicine, Boston University School of Medicine, Boston, MA, USA.
68
Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, UK.
69
Instituto Mexicano del Seguro Social SXXI, Mexico City, Mexico.
70
Department of Pediatrics, Yale University, New Haven, CT, USA.
71
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.
72
Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
73
Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, China.
74
Institute of Human Genetics, Technische Universität München, Munich, Germany.
75
Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
76
Health Science Center, Department of Biochemistry, Faculty of Medicine, Kuwait University, Safat, Kuwait.
77
Department of Pathology and Laboratory Medicine, The Robert Larner M.D. College of Medicine, University of Vermont, Burlington, VT, USA.
78
Department of Biochemistry, The Robert Larner M.D. College of Medicine, University of Vermont, Burlington, VT, USA.
79
Department of Nutrition, Harvard School of Public Health, Boston, MA, USA.
80
Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, USA.
81
Department of Public Health, Aarhus University, Aarhus, Denmark.
82
Danish Diabetes Academy, Odense, Denmark.
83
Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore.
84
Duke-NUS Medical School Singapore, Singapore, Singapore.
85
Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore, Singapore.
86
Department of Medicine, Albert Einstein College of Medicine, New York, NY, USA.
87
Faculty of Natural Science, University of Haifa, Haifa, Israel.
88
Department of Genetics, Albert Einstein College of Medicine, New York, NY, USA.
89
Department of Human Genetics, University of Texas Rio Grande Valley, Edinburg, TX, USA.
90
South Texas Diabetes and Obesity Institute, Brownsville, TX, USA.
91
Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
92
Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
93
Department of Cardiology, Ealing Hospital NHS Trust, Southall, UK.
94
Imperial College Healthcare NHS Trust, Imperial College London, London, UK.
95
Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore, Singapore.
96
Department of Biomedical Science, Hallym University, Chuncheon, South Korea.
97
Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
98
Unidad de Diabetes y Riesgo Cardiovascular, Instituto Nacional de Salud Pública, Cuernavaca, Mexico.
99
Centro de Estudios en Diabetes, Mexico City, Mexico.
100
Institute for Molecular Genetics Finland, University of Helsinki, Helsinki, Finland.
101
National Heart and Lung Institute, Cardiovascular Sciences, Imperial College London, London, UK.
102
Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.
103
Department of Clinical Sciences, Medicine, Lund University, Malmö, Sweden.
104
Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
105
Folkhälsan Research Centre, Helsinki, Finland.
106
Department of Endocrinology, Abdominal Centre, Helsinki University Hospital, Helsinki, Finland.
107
Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
108
Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland.
109
Center for Vascular Prevention, Danube University Krems, Krems, Austria.
110
Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia.
111
Instituto de Investigacion Sanitaria del Hospital Universario LaPaz (IdiPAZ), University Hospital LaPaz, Autonomous University of Madrid, Madrid, Spain.
112
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
113
Instituto Nacional de Ciencias Medicas y Nutricion, Mexico City, Mexico.
114
Center for Non-Communicable Diseases, Karachi, Pakistan.
115
Department of Business Data Convergence, Chungbuk National University, Gyeonggi-do, South Korea.
116
The Mindich Child Health and Development Insititute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
117
Clinical Research Centre, Centre for Molecular Medicine, Ninewells Hospital and Medical School, Dundee, UK.
118
Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
119
Section of Cardiology, Department of Medicine, VA Boston Healthcare, Boston, MA, USA.
120
Brigham and Women's Hospital, Boston, MA, USA.
121
Intramural Administration Management Branch, National Heart Lung and Blood Institute, NIH, Framingham, MA, USA.
122
Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Medical Research Institute, Ninewells Hospital and Medical School, Dundee, UK.
123
Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA.
124
Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, South Korea.
125
Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea.
126
Life Sciences Institute, National University of Singapore, Singapore, Singapore.
127
Department of Statistics and Applied Probability, National University of Singapore, Singapore, Singapore.
128
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
129
Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
130
Instituto de Investigaciones Biomédicas, Departamento de Medicina Genómica y Toxicología, Universidad Nacional Autónoma de México, Mexico City, Mexico.
131
Research Unit of Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
132
German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
133
Deutsches Forschungszentrum für Herz-Kreislauferkrankungen (DZHK), Partner Site Munich Heart Alliance, Munich, Germany.
134
Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Neuherberg, Germany.
135
Department of Medicine, University of Colorado Denver, Aurora, CO, USA.
136
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
137
Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
138
Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
139
Department of Epidemiology, Colorado School of Public Health, Aurora, CO, USA.
140
Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, USA.
141
Department of Laboratory Medicine & Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
142
Blood Systems Research Institute, San Francisco, CA, USA.
143
Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
144
Division of Endocrinology and Metabolism, Department of Medicine, McGill University, Montreal, Quebec, Canada.
145
McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada.
146
Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, USA.
147
Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA, USA.
148
Department of Pediatrics, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
149
Department of Medicine, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
150
Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
151
Department of Genetics, Harvard Medical School, Boston, MA, USA.
152
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
153
Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA.
154
Department of Biostatistics, University of Liverpool, Liverpool, UK.
155
Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, UK.

Abstract

Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791 individuals with type 2 diabetes (T2D) and 24,440 non-diabetic control participants from 5 ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4 genes at exome-wide significance, including a series of more than 30 SLC30A8 alleles that conveys protection against T2D, and in 12 gene sets, including those corresponding to T2D drug targets (P = 6.1 × 10-3) and candidate genes from knockout mice (P = 5.2 × 10-3). Within our study, the strongest T2D gene-level signals for rare variants explain at most 25% of the heritability of the strongest common single-variant signals, and the gene-level effect sizes of the rare variants that we observed in established T2D drug targets will require 75,000-185,000 sequenced cases to achieve exome-wide significance. We propose a method to interpret these modest rare-variant associations and to incorporate these associations into future target or gene prioritization efforts.

PMID:
31118516
PMCID:
PMC6699738
DOI:
10.1038/s41586-019-1231-2
[Indexed for MEDLINE]
Free PMC Article

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