Article open access publication

Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes

Nature Genetics, Springer Nature, ISSN 1061-4036

Volume 50, 4, 2018

DOI:10.1038/s41588-018-0084-1, Dimensions: pub.1103192964, PMC: PMC5898373, PMID: 29632382,

Authors

Zhao, Wei (4)
Chu, Audrey Y (6) (7)
Gan, Wei (1)
Rayner, N. William (1) (5) (9)
Li, Man (12) (13)
Hu, Yao (15)
Zhang, Weihua (17) (18)
Flannick, Jason (20) (21)
Müller-Nurasyid, Martina (27) (28) (29)
Meidtner, Karina (30) (31)
Li, Jin (34)
An, Ping (37)
Demirkan, Ayse (32) (38)
Peloso, Gina Marie (20) (25)
Afzal, Shoaib (22) (48) (49)
Brandslund, Ivan (51) (52)
Hai, Yang (10)
Han, Sohee (24)
Tybjærg-Hansen, Anne (22) (49) (59)
Hivert, Marie-France (21) (60) (61)
Isomaa, Bo (62) (63)
Jäger, Susanne (30) (31)
Jørgensen, Torben (22) (66) (67)
Koistinen, Heikki A (70) (71) (72)
Kriebel, Jennifer (31) (74)
Linneberg, Allan (22) (67) (78)
Liu, Jun (38)
Loh, Marie (18) (79) (80)
Neville, Matt (5) (83)
Nielsen, Sune F. (22) (48) (49)
Rode, Line (48) (49)
Thorand, Barbara (31) (91)
Varbo, Anette (22) (48) (49) (59)
Witte, Daniel R. (92) (93)
Yao, Jie (10)
Young, Robin (90) (94)
Boerwinkle, Eric (45) (96)
Dehghan, Abbas (18) (38)
Deloukas, Panos (47) (99)
Ferrières, Jean (101) (102)
Florez, Jose C. (20) (21) (61)
Kathiresan, Sekar (20) (21) (61)
Kee, Frank (105)
Kuusisto, Johanna (88) (89)
Lindgren, Cecilia M. (1) (5) (20)
Meitinger, Thomas (106) (107)
Moitry, Marie (109) (110)
Morris, Andrew D. (33) (111)
Perola, Markus (71) (113)
Peters, Annette (28) (31) (91)
Ridker, Paul M. (6) (61)
Sheu, Wayne H.-H. (77) (114) (115)
Sladek, Rob (116) (117)
Strauch, Konstantin (29) (119)
Danesh, John (9) (90)
Dupuis, Josée (7) (25)
Franks, Paul W. (23) (61) (86)
Froguel, Philippe (18) (43)
Grallert, Harald (31) (74) (120) (121)
Groop, Leif (23) (113)
Hansen, Torben (22) (52)
Ingelsson, Erik (34) (39)
Karpe, Fredrik (5) (83)
Laakso, Markku (88) (89)
Lind, Lars (39)
Nordestgaard, Børge G. (22) (48) (49)
Psaty, Bruce M (14) (124)
Soranzo, Nicole (9) (90)
Stefansson, Kari (36) (41)
Tuomi, Tiinamaija (63) (72) (113)
Tuomilehto, Jaakko (71) (99) (127) (128)
Barroso, Inês (9) (90)
Saleheen, Danish (4) (103)
Morris, Andrew P. (1) (19) (57)
McCarthy, Mark I. * (1) (5) (83)

* Corresponding author

Affiliations

Organisations

  1. (1) Wellcome Centre for Human Genetics, grid.270683.8
  2. (2) Indiana University – Purdue University Indianapolis, grid.257413.6
  3. (3) Institute of Metabolic Science, grid.470900.a
  4. (4) University of Pennsylvania, grid.25879.31
  5. (5) University of Oxford, grid.4991.5
  6. (6) Brigham and Women's Hospital, grid.62560.37
  7. (7) National Heart Lung and Blood Institute, grid.279885.9
  8. (8) University of Michigan, grid.214458.e
  9. (9) Wellcome Sanger Institute, grid.10306.34
  10. (10) Harbor–UCLA Medical Center, grid.239844.0
  11. (11) Icahn School of Medicine at Mount Sinai, grid.59734.3c
  12. (12) University of Utah, grid.223827.e
  13. (13) Johns Hopkins University, grid.21107.35
  14. (14) University of Washington, grid.34477.33
  15. (15) Shanghai Institutes for Biological Sciences, grid.419092.7
  16. (16) Wake Forest Baptist Medical Center, grid.412860.9
  17. (17) Ealing Hospital, grid.415918.0
  18. (18) Imperial College London, grid.7445.2
  19. (19) University of Liverpool, grid.10025.36
  20. (20) Broad Institute, grid.66859.34
  21. (21) Massachusetts General Hospital, grid.32224.35
  22. (22) University of Copenhagen, grid.5254.6, KU
  23. (23) Lund University, grid.4514.4
  24. (24) Korea National Institute of Health, grid.415482.e
  25. (25) Boston University, grid.189504.1
  26. (26) University of Exeter, grid.8391.3
  27. (27) Department of Medicine I, University Hospital Großhadern, Ludwig Maximilians Universität, Munich, Germany
  28. (28) German Centre for Cardiovascular Research, grid.452396.f
  29. (29) Institute of Genetic Epidemiology, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany
  30. (30) German Institute of Human Nutrition, grid.418213.d
  31. (31) German Center for Diabetes Research, grid.452622.5
  32. (32) Leiden University Medical Center, grid.10419.3d
  33. (33) University of Edinburgh, grid.4305.2
  34. (34) Stanford University, grid.168010.e
  35. (35) Icelandic Heart Association, grid.420802.c
  36. (36) University of Iceland, grid.14013.37
  37. (37) Washington University in St. Louis, grid.4367.6
  38. (38) Erasmus University Medical Center, grid.5645.2
  39. (39) Uppsala University, grid.8993.b
  40. (40) University of Verona, grid.5611.3
  41. (41) deCODE Genetics/Amgen, Inc., Reykjavik, Iceland
  42. (42) Institute of Genetic Epidemiology, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
  43. (43) University of Lille, grid.503422.2
  44. (44) University of North Carolina System, grid.410711.2
  45. (45) The University of Texas Health Science Center at Houston, grid.267308.8
  46. (46) Penn State Milton S. Hershey Medical Center, grid.240473.6
  47. (47) Queen Mary University of London, grid.4868.2
  48. (48) Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
  49. (49) Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark
  50. (50) Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  51. (51) Vejle Sygehus, grid.417271.6, Southern Denmark Region
  52. (52) University of Southern Denmark, grid.10825.3e, SDU
  53. (53) Hallym University, grid.256753.0
  54. (54) Medical Department, Lillebælt Hospital Vejle, Vejle, Denmark
  55. (55) University College London, grid.83440.3b
  56. (56) Charité, grid.6363.0
  57. (57) University of Tartu, grid.10939.32
  58. (58) Catholic University of the Sacred Heart, grid.8142.f
  59. (59) Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  60. (60) Université de Sherbrooke, grid.86715.3d
  61. (61) Harvard University, grid.38142.3c
  62. (62) Malmska Municipal Health Care Center and Hospital, Jakobstad, Finland
  63. (63) Folkhälsans Forskningscentrum, grid.428673.c
  64. (64) Danish National Institute of Public Health, grid.459286.4
  65. (65) Steno Diabetes Center, grid.419658.7, Capital Region
  66. (66) Aalborg University, grid.5117.2, AAU
  67. (67) Research Centre for Prevention and Health, grid.415878.7, Capital Region
  68. (68) Diabetes Center, Vaasa Health Care Center, Vaasa, Finland
  69. (69) Vaasa Central Hospital, grid.417201.1
  70. (70) Minerva Foundation, grid.452540.2
  71. (71) National Institute for Health and Welfare, grid.14758.3f
  72. (72) Helsinki University Central Hospital, grid.15485.3d
  73. (73) Leipzig University, grid.9647.c
  74. (74) Research Unit of Molecular Epidemiology, Institute of Epidemiology II, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany
  75. (75) Innsbruck Medical University, grid.5361.1
  76. (76) University of Colorado Anschutz Medical Campus, grid.430503.1
  77. (77) Taichung Veterans General Hospital, grid.410764.0
  78. (78) Rigshospitalet, grid.475435.4, Capital Region
  79. (79) Agency for Science, Technology and Research, grid.185448.4
  80. (80) University of Oulu, grid.10858.34
  81. (81) National and Kapodistrian University of Athens, grid.5216.0
  82. (82) University of Southern California, grid.42505.36
  83. (83) NIHR Oxford Musculoskeletal Biomedical Research Centre, grid.454382.c
  84. (84) German Diabetes Center - Leibniz Institute for Diabetes Research at Heinrich Heine University Düsseldorf, grid.429051.b
  85. (85) University of Virginia, grid.27755.32
  86. (86) Umeå University, grid.12650.30
  87. (87) King's College London, grid.13097.3c
  88. (88) Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
  89. (89) Kuopio University Hospital, grid.410705.7
  90. (90) University of Cambridge, grid.5335.0
  91. (91) Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany
  92. (92) Aarhus University, grid.7048.b, AU
  93. (93) Danish Diabetes Academy, grid.484078.7
  94. (94) University of Glasgow, grid.8756.c
  95. (95) Institut Pasteur de Lille, INSERM U1167, Université Lille Nord de France, Lille, France
  96. (96) Baylor College of Medicine, grid.39382.33
  97. (97) National Human Genome Research Institute, grid.280128.1
  98. (98) Harokopio University, grid.15823.3d
  99. (99) King Abdulaziz University, grid.412125.1
  100. (100) University of Insubria, grid.18147.3b
  101. (101) Délégation Midi-Pyrénées, Limousin, grid.457379.b
  102. (102) Hôpital Rangueil, grid.414295.f
  103. (103) Center for Non-Communicable Diseases, grid.497620.e
  104. (104) National Institutes of Health, grid.94365.3d
  105. (105) Queen's University Belfast, grid.4777.3
  106. (106) Institute of Human Genetics, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany
  107. (107) Technical University of Munich, grid.6936.a
  108. (108) University of North Carolina at Chapel Hill, grid.10698.36
  109. (109) Hôpitaux Universitaires de Strasbourg, grid.412220.7
  110. (110) University of Strasbourg, grid.11843.3f
  111. (111) Ninewells Hospital, grid.416266.1
  112. (112) University of Aberdeen, grid.7107.1
  113. (113) University of Helsinki, grid.7737.4
  114. (114) National Defense Medical Center, grid.260565.2
  115. (115) National Yang Ming University, grid.260770.4
  116. (116) McGill University, grid.14709.3b
  117. (117) McGill University and Génome Québec Innovation Centre, grid.411640.6
  118. (118) Division of Population Health Sciences, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK
  119. (119) Ludwig Maximilian University of Munich, grid.5252.0
  120. (120) Clinical Cooperation Group Nutrigenomics and Type 2 Diabetes, Helmholtz Zentrum München, Technical University of Munich, Munich, Germany
  121. (121) Helmholtz Zentrum München, grid.4567.0
  122. (122) Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK
  123. (123) University of Minnesota, grid.17635.36
  124. (124) Kaiser Permanente Washington Health Research Institute, grid.488833.c
  125. (125) Kuopion Liikuntalääketieteen Tutkimuslaitos, grid.419013.e
  126. (126) University Hospital Leipzig, grid.411339.d
  127. (127) Danube University Krems, grid.15462.34
  128. (128) Dasman Diabetes Institute, grid.452356.3
  129. (129) University of Mississippi Medical Center, grid.410721.1
  130. (130) Cedars-Sinai Medical Center, grid.50956.3f

Description

We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10-7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent 'false leads' with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.

Funders

Research Categories

Main Subject Area

Fields of Research

Links & Metrics

NORA University Profiles

University of Copenhagen

University of Southern Denmark

Aalborg University

Aarhus University

Danish Open Access Indicator

2018: Realized

Research area: Medicine

Danish Bibliometrics Indicator

2018: Level 3

Research area: Medicine

Dimensions Citation Indicators

Times Cited: 124

Field Citation Ratio (FCR): 39.57

Relative Citation ratio (RCR): 8.51

Open Access Info

Green, Accepted