Article open access publication

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

Nature, Springer Nature, ISSN 1476-4687

Volume 570, 7759, 2019

DOI:10.1038/s41586-019-1231-2, Dimensions: pub.1115158118, PMC: PMC6699738, PMID: 31118516,

Authors

Flannick, Jason A * (1) (2) (3)
Mercader, Josep Maria (2) (3) (4)
Udler, Miriam Sargon (2) (3) (4)
Mahajan, Anubha (7) (8)
Boerwinkle, Eric A (12) (13)
Chen, Ling (2) (4)
Elliott, Amanda (2) (3) (4)
Han, Sohee (21)
Jørgensen, Marit Eika (24) (25) (26)
Koistinen, Heikki A (27) (28) (29)
Linneberg, Allan R (33) (34) (35)
Liu, Jianjun (36) (37)
Lyssenko, Valeriya (38) (39)
Psaty, Bruce M (14) (45)
Rayner, Nigel William (7) (8) (46)
Wong, Tien-Yin (37) (57) (58)
Atzmon, Gil (59) (60)
Blangero, John C (61) (62)
Chambers, John C. (64) (65)
Laakso, Markku H (30) (31)
Tai, E Shyong (37) (58)
Tuomi, Tiinamaija (28) (70) (73)
Tuomilehto, Jaakko (29) (74) (75) (76)
Dupuis, Josée (22) (23)
O'Donnell, Christopher J (2) (23) (81) (82)
Park, Kyong Soo (65) (83)
Saleheen, Danish (54) (78)
Gieger, Christian (86) (87)
Meitinger, Thomas (50) (51) (88)
Hansen, Torben (26) (35)
Seielstad, Mark T (93) (94)
Sladek, Rob (95) (96)
Meigs, James B (2) (3) (4)
Altshuler, David (2) (3) (4) (99)
Morris, Andrew P. (7) (100)
Florez, Jose Carlos (2) (3) (4)
Mccarthy, Mark Ian (7) (8) (101)

* Corresponding author

Affiliations

Organisations

  1. (1) Boston Children's Hospital, grid.2515.3
  2. (2) Harvard University, grid.38142.3c
  3. (3) Broad Institute, grid.66859.34
  4. (4) Massachusetts General Hospital, grid.32224.35
  5. (5) Institute for Biomedicine, Eurac Research, Bolzano, Italy
  6. (6) University of Michigan, grid.214458.e
  7. (7) Wellcome Centre for Human Genetics, grid.270683.8
  8. (8) University of Oxford, grid.4991.5
  9. (9) Indiana University – Purdue University Indianapolis, grid.257413.6
  10. (10) Regeneron (United States), grid.418961.3
  11. (11) National Institute of Genomic Medicine, grid.452651.1
  12. (12) Baylor College of Medicine, grid.39382.33
  13. (13) The University of Texas Health Science Center at Houston, grid.267308.8
  14. (14) University of Washington, grid.34477.33
  15. (15) University of Mississippi Medical Center, grid.410721.1
  16. (16) The University of Texas Health Science Center at San Antonio, grid.267309.9
  17. (17) Cincinnati Children's Hospital Medical Center, grid.239573.9
  18. (18) George Washington University, grid.253615.6
  19. (19) University of Chicago, grid.170205.1
  20. (20) University of Minnesota, grid.17635.36
  21. (21) Korea National Institute of Health, grid.415482.e
  22. (22) Boston University, grid.189504.1
  23. (23) National Heart Lung and Blood Institute, grid.279885.9
  24. (24) Steno Diabetes Center, grid.419658.7, Capital Region
  25. (25) University of Greenland, grid.449721.d
  26. (26) University of Southern Denmark, grid.10825.3e, SDU
  27. (27) Minerva Foundation, grid.452540.2
  28. (28) Helsinki University Hospital, grid.15485.3d
  29. (29) Finnish Institute for Health and Welfare, grid.14758.3f
  30. (30) Kuopio University Hospital, grid.410705.7
  31. (31) University of Eastern Finland, grid.9668.1
  32. (32) Geisinger Health System, grid.280776.c
  33. (33) Bispebjerg Hospital, grid.411702.1, Capital Region
  34. (34) Rigshospitalet, grid.475435.4, Capital Region
  35. (35) University of Copenhagen, grid.5254.6, KU
  36. (36) Genome Institute of Singapore, grid.418377.e
  37. (37) National University of Singapore, grid.4280.e
  38. (38) University of Bergen, grid.7914.b
  39. (39) Lund University, grid.4514.4
  40. (40) University of North Carolina at Chapel Hill, grid.10698.36
  41. (41) Wake Forest University, grid.241167.7
  42. (42) Seattle Children's Hospital, grid.240741.4
  43. (43) Johns Hopkins University, grid.21107.35
  44. (44) Icahn School of Medicine at Mount Sinai, grid.59734.3c
  45. (45) Kaiser Permanente Washington Health Research Institute, grid.488833.c
  46. (46) Wellcome Sanger Institute, grid.10306.34
  47. (47) Mexican Social Security Institute, grid.419157.f
  48. (48) Yale University, grid.47100.32
  49. (49) Chinese University of Hong Kong, grid.10784.3a
  50. (50) Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
  51. (51) Technical University of Munich, grid.6936.a
  52. (52) Kuwait University, grid.411196.a
  53. (53) University of Vermont, grid.59062.38
  54. (54) University of Pennsylvania, grid.25879.31
  55. (55) Aarhus University, grid.7048.b, AU
  56. (56) Danish Diabetes Academy, grid.484078.7
  57. (57) Singapore National Eye Center, grid.419272.b
  58. (58) Duke NUS Graduate Medical School, grid.428397.3
  59. (59) University of Haifa, grid.18098.38
  60. (60) Albert Einstein College of Medicine, grid.251993.5
  61. (61) South Texas Diabetes and Obesity Institute, Brownsville, TX, USA
  62. (62) The University of Texas Rio Grande Valley, grid.449717.8
  63. (63) National Human Genome Research Institute, grid.280128.1
  64. (64) Ealing Hospital NHS Trust, grid.412922.e
  65. (65) Imperial College London, grid.7445.2
  66. (66) Hallym University, grid.256753.0
  67. (67) Hadassah Medical Center, grid.17788.31
  68. (68) Instituto Nacional de Salud Pública, grid.415771.1
  69. (69) Centro de Estudios en Diabetes, Mexico City, Mexico
  70. (70) University of Helsinki, grid.7737.4
  71. (71) Seoul National University Hospital, grid.412484.f
  72. (72) King's College London, grid.13097.3c
  73. (73) Folkhälsans Forskningscentrum, grid.428673.c
  74. (74) Autonomous University of Madrid, grid.5515.4
  75. (75) Danube University Krems, grid.15462.34
  76. (76) King Abdulaziz University, grid.412125.1
  77. (77) Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, grid.416850.e
  78. (78) Center for Non-Communicable Diseases, grid.497620.e
  79. (79) Chungbuk National University, grid.254229.a
  80. (80) Ninewells Hospital, grid.416266.1
  81. (81) Brigham and Women's Hospital, grid.62560.37
  82. (82) Section of Cardiology, Department of Medicine, VA Boston Healthcare, Boston, MA, USA
  83. (83) Seoul National University, grid.31501.36
  84. (84) University of Southern California, grid.42505.36
  85. (85) National Autonomous University of Mexico, grid.9486.3
  86. (86) German Center for Diabetes Research, grid.452622.5
  87. (87) Research Unit of Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
  88. (88) Deutsches Forschungszentrum für Herz-Kreislauferkrankungen (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
  89. (89) Ludwig-Maximilians-Universität München, grid.5252.0
  90. (90) University of Colorado Anschutz Medical Campus, grid.430503.1
  91. (91) Colorado School of Public Health, grid.414594.9
  92. (92) Vanderbilt University, grid.152326.1
  93. (93) Blood Systems Research Institute, grid.280902.1
  94. (94) University of California, San Francisco, grid.266102.1
  95. (95) McGill University, grid.14709.3b
  96. (96) McGill University and Génome Québec Innovation Centre, grid.411640.6
  97. (97) University of Virginia, grid.27755.32
  98. (98) Los Angeles Biomedical Research Institute, grid.279946.7
  99. (99) Massachusetts Institute of Technology, grid.116068.8
  100. (100) University of Liverpool, grid.10025.36
  101. (101) NIHR Oxford Musculoskeletal Biomedical Research Centre, grid.454382.c

Description

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.

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University of Southern Denmark

University of Copenhagen

Aarhus University

Danish Open Access Indicator

2019: Realized

Research area: Medicine

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2019: Level 3

Research area: Medicine

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Times Cited: 86

Field Citation Ratio (FCR): 35.5

Relative Citation ratio (RCR): 8.74

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