Article open access publication

The genetic architecture of type 2 diabetes

Nature, Springer Nature, ISSN 1476-4687

Volume 536, 7614, 2016

DOI:10.1038/nature18642, Dimensions: pub.1036558635, PMC: PMC5034897, PMID: 27398621,

Authors

Flannick, Jason (4) (5)
Ma, Clement (3) (8)
Perry, John R B (6) (10) (11) (12)
Sim, Xue Ling (3) (8)
Rayner, N. William (6) (9) (13)
Cingolani, Pablo (14) (15)
Locke, Adam E. (3) (8)
Dupuis, Josee (17) (18)
Lindgren, Cecilia M. (4) (6) (8)
Chen, Han (18) (20)
Kumar, Ashish (6) (21)
Müller-Nurasyid, Martina (22) (23) (24) (25)
Gamazon, Eric R (8) (27)
Chen, Peng (29)
Huang, Jinyan (8) (20)
Hu, Cheng (34)
Ikram, Mohammad Kamran (29) (35) (36)
Nagai, Yoshihiko (14) (15) (37)
Wang, Xu (29)
Yoon, Joon (28)
Zhang, Weihua (38) (39)
Kuusisto, Johanna (44) (45)
Purcell, Shaun (4) (5) (51)
Zhao, Wei (41)
Danesh, John (13) (53)
Saleheen, Danish (41) (55)
Arya, Rector (8) (43)
Aung, Tin (29) (35) (36)
Navarro, Carmen (57) (58)
Cheng, Ching-Y U (29) (35) (36)
Khor, Chiea Chuen (29) (35) (63)
Liu, Jianjun (29) (63)
Loh, Marie (8) (39) (66) (67)
Tan, Sian-Tsung (38) (39)
Thameem, Farook (8) (43)
Wong, Tien Yin (29) (35) (36)
Herder, Christian (72) (73)
Brandslund, Ivan (74) (75)
Koistinen, Heikki A (76) (77) (78)
Esko, Tõnu (4) (20) (80) (81)
Hakaste, Liisa (78) (82) (83)
Jørgensen, Torben (26) (85) (86)
Ladenvall, Claes (8) (32)
Kriebel, Jennifer (23) (72)
Linneberg, Allan (26) (86) (90)
Neville, Matt (9) (91)
Qi, Lu (8) (20) (92)
Qi, Qibin (20) (40)
Roden, Michael (72) (73) (93)
Swift, Amy (19)
DePristo, Mark (4) (8)
Hrabé de Angelis, Martin (23) (72) (95)
Deloukas, Panos (96) (97)
Jun, Goo (3) (16)
Thorand, Barbara (23) (72)
Hansen, Torben (26) (75)
Meisinger, Christa (23) (72)
Isomaa, Bo (82) (98)
Karpe, Fredrik (9) (91)
Peters, Annette (23) (24) (72)
Huth, Cornelia (23) (72)
Tuomilehto, Jaakko (8) (77) (97) (101) (102)
Sandhu, Manjinder (13) (53)
Froguel, Philippe (39) (64)
Barroso, Inês (13) (53)
Grallert, Harald (23) (72)
Walker, Mark (111)
Ingelsson, Erik (6) (8) (49)
Illig, Thomas (23) (112)
Franks, Paul W. (20) (32) (94)
Prokopenko, Inga (6) (9) (39)
Lind, Lars (49)
Gloyn, Anna L. (6) (9) (91)
Tuomi, Tiinamaija (78) (82) (83)
Lee, Jong-Young (8) (30)
Donnelly, Peter (6) (9)
Morris, Andrew D. (79) (113)
Atzmon, Gil (40) (114)
Chambers, John C. (38) (39)
Laakso, Markku (44) (45)
Strom, Tim M. (71) (95)
McVean, Gilean (6) (9)
Seielstad, Mark (116) (117)
Cox, Nancy J. (8) (27)
Sladek, Rob (14) (15)
Meitinger, Thomas (71) (95)
Groop, Leif (32) (83)
Florez, Jose C. (4) (5) (20)
Morris, Andrew P. (6) (81) (119)
Altshuler, David (4) (5) (7) (8) (20)
McCarthy, Mark I. * (6) (9) (91)

* Corresponding author

Affiliations

Organisations

  1. (1) European Academy of Bozen, grid.418908.c
  2. (2) Innsbruck Medical University, grid.5361.1
  3. (3) University of Michigan, grid.214458.e
  4. (4) Broad Institute, grid.66859.34
  5. (5) Massachusetts General Hospital, grid.32224.35
  6. (6) Wellcome Centre for Human Genetics, grid.270683.8
  7. (7) Massachusetts Institute of Technology, grid.116068.8
  8. (8) † Present addresses are provided in the Supplementary Information.
  9. (9) University of Oxford, grid.4991.5
  10. (10) King's College London, grid.13097.3c
  11. (11) Institute of Metabolic Science, grid.470900.a
  12. (12) University of Exeter, grid.8391.3
  13. (13) Wellcome Sanger Institute, grid.10306.34
  14. (14) McGill University, grid.14709.3b
  15. (15) McGill University and Génome Québec Innovation Centre, grid.411640.6
  16. (16) The University of Texas Health Science Center at Houston, grid.267308.8
  17. (17) National Heart Lung and Blood Institute, grid.279885.9
  18. (18) Boston University, grid.189504.1
  19. (19) National Human Genome Research Institute, grid.280128.1
  20. (20) Harvard University, grid.38142.3c
  21. (21) Chronic Disease Epidemiology, Swiss Tropical and Public Health Institute, University of Basel, Basel, Switzerland
  22. (22) Department of Medicine I, University Hospital Grosshadern, Ludwig Maximilians Universität, Munich, Germany
  23. (23) Helmholtz Zentrum München, grid.4567.0
  24. (24) German Centre for Cardiovascular Research, grid.452396.f
  25. (25) Ludwig Maximilian University of Munich, grid.5252.0
  26. (26) University of Copenhagen, grid.5254.6, KU
  27. (27) Department of Medicine, Section of Genetic Medicine, The University of Chicago, Chicago, Illinois, USA
  28. (28) Seoul National University, grid.31501.36
  29. (29) National University of Singapore, grid.4280.e
  30. (30) Korea National Institute of Health, grid.415482.e
  31. (31) Jackson Laboratory, grid.249880.f
  32. (32) Lund University, grid.4514.4
  33. (33) University of Colorado Anschutz Medical Campus, grid.430503.1
  34. (34) Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
  35. (35) Singapore National Eye Center, grid.419272.b
  36. (36) Duke NUS Graduate Medical School, grid.428397.3
  37. (37) McGill University Health Centre, grid.63984.30
  38. (38) Ealing Hospital NHS Trust, grid.412922.e
  39. (39) Imperial College London, grid.7445.2
  40. (40) Albert Einstein College of Medicine, grid.251993.5
  41. (41) University of Pennsylvania, grid.25879.31
  42. (42) South Texas Veterans Health Care System, grid.280682.6
  43. (43) The University of Texas Health Science Center at San Antonio, grid.267309.9
  44. (44) University of Eastern Finland, grid.9668.1
  45. (45) Kuopio University Hospital, grid.410705.7
  46. (46) Wake Forest University, grid.241167.7
  47. (47) Centre for research in epidemiology and population health, grid.463845.8
  48. (48) German Institute of Human Nutrition, grid.418213.d
  49. (49) Uppsala University, grid.8993.b
  50. (50) Centre for Chronic Disease Control, grid.417995.7
  51. (51) Icahn School of Medicine at Mount Sinai, grid.59734.3c
  52. (52) University of Washington, grid.34477.33
  53. (53) University of Cambridge, grid.5335.0
  54. (54) Chinese University of Hong Kong, grid.10784.3a
  55. (55) Center for Non-Communicable Diseases, grid.497620.e
  56. (56) Baylor College of Medicine, grid.39382.33
  57. (57) Instituto Murciano de Investigación Biosanitaria, grid.452553.0
  58. (58) University of Murcia, grid.10586.3a
  59. (59) Istituto per lo Studio e la Prevenzione Oncologica, grid.417623.5
  60. (60) University of Mississippi Medical Center, grid.410721.1
  61. (61) The University of Texas Rio Grande Valley, grid.449717.8
  62. (62) Texas Biomedical Research Institute, grid.250889.e
  63. (63) Genome Institute of Singapore, grid.418377.e
  64. (64) University of Lille, grid.503422.2
  65. (65) University Medical Center Utrecht, grid.7692.a
  66. (66) Agency for Science, Technology and Research, grid.185448.4
  67. (67) University of Oulu, grid.10858.34
  68. (68) Jackson State University, grid.257990.0
  69. (69) Haukeland University Hospital, grid.412008.f
  70. (70) University of Bergen, grid.7914.b
  71. (71) Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
  72. (72) German Center for Diabetes Research, grid.452622.5
  73. (73) German Diabetes Center - Leibniz Institute for Diabetes Research at Heinrich Heine University Düsseldorf, grid.429051.b
  74. (74) Vejle Sygehus, grid.417271.6, Southern Denmark Region
  75. (75) University of Southern Denmark, grid.10825.3e, SDU
  76. (76) Minerva Foundation, grid.452540.2
  77. (77) National Institute for Health and Welfare, grid.14758.3f
  78. (78) Helsinki University Central Hospital, grid.15485.3d
  79. (79) Ninewells Hospital, grid.416266.1
  80. (80) Boston Children's Hospital, grid.2515.3
  81. (81) University of Tartu, grid.10939.32
  82. (82) Folkhälsans Forskningscentrum, grid.428673.c
  83. (83) University of Helsinki, grid.7737.4
  84. (84) Steno Diabetes Center, grid.419658.7, Capital Region
  85. (85) Aalborg University, grid.5117.2, AAU
  86. (86) Research Centre for Prevention and Health, grid.415878.7, Capital Region
  87. (87) Diabetes Center, Vaasa Health Care Center, Vaasa, Finland
  88. (88) Vaasa Central Hospital, grid.417201.1
  89. (89) Aarhus University, grid.7048.b, AU
  90. (90) Rigshospitalet, grid.475435.4, Capital Region
  91. (91) NIHR Oxford Musculoskeletal Biomedical Research Centre, grid.454382.c
  92. (92) Brigham and Women's Hospital, grid.62560.37
  93. (93) Heinrich Heine University Düsseldorf, grid.411327.2
  94. (94) Umeå University, grid.12650.30
  95. (95) Technical University of Munich, grid.6936.a
  96. (96) Queen Mary University of London, grid.4868.2
  97. (97) King Abdulaziz University, grid.412125.1
  98. (98) Department of Social Services and Health Care, Jakobstad, Finland
  99. (99) Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK
  100. (100) Kuopion Liikuntalääketieteen Tutkimuslaitos, grid.419013.e
  101. (101) Autonomous University of Madrid, grid.5515.4
  102. (102) Danube University Krems, grid.15462.34
  103. (103) University of Southern California, grid.42505.36
  104. (104) Institute of Genomics and Integrative Biology, grid.417639.e
  105. (105) Hallym University, grid.256753.0
  106. (106) Centre for Cellular and Molecular Biology, grid.417634.3
  107. (107) George Washington University, grid.253615.6
  108. (108) University of Maryland, Baltimore, grid.411024.2
  109. (109) All India Institute of Medical Sciences, grid.413618.9
  110. (110) Hadassah Medical Center, grid.17788.31
  111. (111) Newcastle University, grid.1006.7
  112. (112) Hannover Medical School, grid.10423.34
  113. (113) University of Edinburgh, grid.4305.2
  114. (114) University of Haifa, grid.18098.38
  115. (115) Departments of Medicine and Human Genetics, The University of Chicago, Chicago, Illinois, USA
  116. (116) Blood Systems Research Institute, grid.280902.1
  117. (117) University of California, San Francisco, grid.266102.1
  118. (118) University of North Carolina at Chapel Hill, grid.10698.36
  119. (119) University of Liverpool, grid.10025.36

Description

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.

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Times Cited: 591

Field Citation Ratio (FCR): 98.87

Relative Citation ratio (RCR): 30.53

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