Article open access publication

A Low-Frequency Inactivating Akt2 Variant Enriched in the Finnish Population is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk.

Diabetes, American Diabetes Association, ISSN 0012-1797

Volume 66, 7, 2017

DOI:10.2337/db16-1329, Dimensions: pub.1084404974, PMC: PMC5482074, PMID: 28341696,

Authors

Manning, Alisa (1) (2) (3)
Sim, Xue Ling (6) (7)
Tukiainen, Taru (1) (2) (3)
Cingolani, Pablo (11) (12)
Pers, Tune H (1) (9) (13) (14)
Viñuela, Ana (15) (16)
Brown, Andrew A (17) (18)
Wu, Ying (4)
Flannick, Jason (1) (2)
Gamazon, Eric R (19) (20)
Gaulton, Kyle J (10) (21)
Kumar, Ashish (10) (22)
Perry, John R B (10) (24) (25)
Rayner, N William (10) (26) (27)
Robertson, Neil R (10) (27)
Eriksson, Johan G (28) (29) (30) (31) (32)
Palotie, Aarno (1) (2) (32)
Raitakari, Olli T (34) (35)
Wessel, Jennifer (36) (37)
Jun, Goo (6)
Hrabé de Angelis, Martin (41) (42) (43)
Purcell, Shaun (1) (2) (44)
Strom, Tim M (45) (47)
Brandslund, Ivan (48) (49)
Lakka, Timo A (50) (51) (52)
Franks, Paul W (3) (23) (54)
Esko, Tõnu (1) (3) (14) (60)
Swift, Amy (40)
Atzmon, Gil (62) (63)
Thorand, Barbara (42) (43)
Peters, Annette (42) (43) (66)
Roden, Michael (43) (67)
Müller-Nurasyid, Martina (42) (65) (66) (68)
Kriebel, Jennifer (42) (43)
Illig, Thomas (42) (69)
Grallert, Harald (42) (43)
Tan, Sian-Tsung (73) (74)
Loh, Marie (73) (75) (76)
Chambers, John C (73) (74)
Sehmi, Jobanpreet (73) (74)
Qi, Qibin (3) (62)
Qi, Lu (3) (38)
Wong, Tien Yin (7) (82)
Liu, Jianjun (7) (83)
Khor, Chiea Chuen (7) (82) (83)
Cheng, Ching-Yu (7) (82) (84)
Tai, E Shyong (7) (84)
Aung, Tin (7) (82)
Linneberg, Allan (9) (85)
Isomaa, Bo (29) (86)
Meitinger, Thomas (45) (47) (66)
Tuomi, Tiinamaija (29) (30)
Owen, Katharine R (27) (91)
Barroso, Inês (26) (90)
Donnelly, Peter J (10) (27)
Hu, Cheng (99)
Sandhu, Manjinder (26) (90)
Sladek, Rob (11) (12)
Koistinen, Heikki A (30) (31) (103)
Prokopenko, Inga (10) (27) (73)
Lind, Lars (58)
Ingelsson, Erik (58) (104)
Tuomilehto, Jaakko (31) (105) (106) (107)
Karpe, Fredrik (27) (91)
Jørgensen, Torben (85) (108)
Hansen, Torben (9) (48)
Kuusisto, Johanna (50) (52)
Seielstad, Mark (110) (111)
Dupuis, Josee (112) (113)
Ripatti, Samuli (18) (32)
Florez, Jose C (1) (2) (3)
Meigs, James B (1) (2) (3)
Laakso, Markku (50) (52)
Morris, Andrew P (10) (60) (114)
Altshuler, David (1) (2) (3) (115)
McCarthy, Mark I (10) (27) (91)
Gloyn, Anna L (10) (27) (91)
Lindgren, Cecilia M (1) (10) (27)

Affiliations

Organisations

  1. (1) Broad Institute, grid.66859.34
  2. (2) Massachusetts General Hospital, grid.32224.35
  3. (3) Harvard University, grid.38142.3c
  4. (4) University of North Carolina at Chapel Hill, grid.10698.36
  5. (5) The University of Texas Health Science Center at Houston, grid.267308.8
  6. (6) University of Michigan, grid.214458.e
  7. (7) National University of Singapore, grid.4280.e
  8. (8) 23andMe (United States), grid.420283.f
  9. (9) University of Copenhagen, grid.5254.6, KU
  10. (10) Wellcome Centre for Human Genetics, grid.270683.8
  11. (11) McGill University, grid.14709.3b
  12. (12) McGill University and Génome Québec Innovation Centre, grid.411640.6
  13. (13) State Serum Institute, grid.6203.7
  14. (14) Boston Children's Hospital, grid.2515.3
  15. (15) University of Geneva, grid.8591.5
  16. (16) King's College London, grid.13097.3c
  17. (17) Oslo University Hospital, grid.55325.34
  18. (18) Wellcome Trust Sanger Institute, Hinxton, U.K.
  19. (19) Academic Medical Center, grid.5650.6
  20. (20) Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL.
  21. (21) University of California, San Diego, grid.266100.3
  22. (22) Chronic Disease Epidemiology Unit, Swiss Tropical and Public Health Institute, University of Basel, Basel, Switzerland.
  23. (23) Lund University, grid.4514.4
  24. (24) University of Exeter, grid.8391.3
  25. (25) Institute of Metabolic Science, grid.470900.a
  26. (26) Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, U.K.
  27. (27) University of Oxford, grid.4991.5
  28. (28) Vaasa Central Hospital, grid.417201.1
  29. (29) Folkhälsans Forskningscentrum, grid.428673.c
  30. (30) Helsinki University Central Hospital, grid.15485.3d
  31. (31) National Institute for Health and Welfare, grid.14758.3f
  32. (32) University of Helsinki, grid.7737.4
  33. (33) Tampere University, grid.502801.e
  34. (34) Turku University Hospital, grid.410552.7
  35. (35) University of Turku, grid.1374.1
  36. (36) Department of Epidemiology, Fairbanks School of Public Health, Indianapolis, IN.
  37. (37) Indiana University – Purdue University Indianapolis, grid.257413.6
  38. (38) Brigham and Women's Hospital, grid.62560.37
  39. (39) Cedars-Sinai Medical Center, grid.50956.3f
  40. (40) National Human Genome Research Institute, grid.280128.1
  41. (41) Technical University of Munich, grid.6936.a
  42. (42) Helmholtz Zentrum München, grid.4567.0
  43. (43) German Center for Diabetes Research, grid.452622.5
  44. (44) Icahn School of Medicine at Mount Sinai, grid.59734.3c
  45. (45) Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
  46. (46) University of Washington, grid.34477.33
  47. (47) Institute of Human Genetics, Technische Universität München, Neuherberg, Germany.
  48. (48) University of Southern Denmark, grid.10825.3e, SDU
  49. (49) Vejle Sygehus, grid.417271.6, Southern Denmark Region
  50. (50) University of Eastern Finland, grid.9668.1
  51. (51) Kuopion Liikuntalääketieteen Tutkimuslaitos, grid.419013.e
  52. (52) Kuopio University Hospital, grid.410705.7
  53. (53) Ninewells Hospital, grid.416266.1
  54. (54) Umeå University, grid.12650.30
  55. (55) Texas Biomedical Research Institute, grid.250889.e
  56. (56) The University of Texas Health Science Center at San Antonio, grid.267309.9
  57. (57) South Texas Veterans Health Care System, grid.280682.6
  58. (58) Uppsala University, grid.8993.b
  59. (59) Wake Forest University, grid.241167.7
  60. (60) University of Tartu, grid.10939.32
  61. (61) Program in Personalized and Genomic Medicine, Department of Medicine, University of Maryland, Baltimore, MD.
  62. (62) Albert Einstein College of Medicine, grid.251993.5
  63. (63) University of Haifa, grid.18098.38
  64. (64) Hadassah Medical Center, grid.17788.31
  65. (65) Ludwig Maximilian University of Munich, grid.5252.0
  66. (66) German Centre for Cardiovascular Research, grid.452396.f
  67. (67) German Diabetes Center - Leibniz Institute for Diabetes Research at Heinrich Heine University Düsseldorf, grid.429051.b
  68. (68) Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany.
  69. (69) Hannover Medical School, grid.10423.34
  70. (70) University of Mississippi Medical Center, grid.410721.1
  71. (71) Jackson State University, grid.257990.0
  72. (72) Pirkanmaa Hospital District, grid.415018.9
  73. (73) Imperial College London, grid.7445.2
  74. (74) Department of Cardiology, Ealing Hospital NHS Trust, Southall, U.K.
  75. (75) Agency for Science, Technology and Research, grid.185448.4
  76. (76) University of Oulu, grid.10858.34
  77. (77) Hallym University, grid.256753.0
  78. (78) Ministry of Health and Welfare, grid.452940.e
  79. (79) Center for Genome Science, Korea National Research Institute of Health, Chungcheongbuk-do, Republic of Korea.
  80. (80) Vaasa Health Care Center, Vaasa, Finland.
  81. (81) Baylor College of Medicine, grid.39382.33
  82. (82) Singapore National Eye Center, grid.419272.b
  83. (83) Genome Institute of Singapore, grid.418377.e
  84. (84) Duke NUS Graduate Medical School, grid.428397.3
  85. (85) Rigshospitalet, grid.475435.4, Capital Region
  86. (86) Department of Social Services and Health Care, Jakobstad, Finland.
  87. (87) Steno Diabetes Center, grid.419658.7, Capital Region
  88. (88) Aarhus University, grid.7048.b, AU
  89. (89) Queen Mary University of London, grid.4868.2
  90. (90) University of Cambridge, grid.5335.0
  91. (91) NIHR Oxford Musculoskeletal Biomedical Research Centre, grid.454382.c
  92. (92) Newcastle University, grid.1006.7
  93. (93) Institute of Genomics and Integrative Biology, grid.417639.e
  94. (94) Chinese University of Hong Kong, grid.10784.3a
  95. (95) Centre for Cellular and Molecular Biology, grid.417634.3
  96. (96) Centre for Chronic Disease Control, grid.417995.7
  97. (97) University of Colorado Anschutz Medical Campus, grid.430503.1
  98. (98) Institut de Biologie de Lille, grid.418183.7
  99. (99) Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
  100. (100) Seoul National University, grid.31501.36
  101. (101) All India Institute of Medical Sciences, grid.413618.9
  102. (102) University of Southern California, grid.42505.36
  103. (103) Minerva Foundation, grid.452540.2
  104. (104) Stanford University, grid.168010.e
  105. (105) Danube University Krems, grid.15462.34
  106. (106) Dasman Diabetes Institute, grid.452356.3
  107. (107) King Abdulaziz University, grid.412125.1
  108. (108) Aalborg University, grid.5117.2, AAU
  109. (109) Departments of Medicine and Human Genetics, The University of Chicago, Chicago, IL.
  110. (110) Blood Systems Research Institute, grid.280902.1
  111. (111) University of California, San Francisco, grid.266102.1
  112. (112) Boston University, grid.189504.1
  113. (113) National Heart Lung and Blood Institute, grid.279885.9
  114. (114) University of Liverpool, grid.10025.36
  115. (115) Massachusetts Institute of Technology, grid.116068.8

Description

To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.

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University of Copenhagen

University of Southern Denmark

Aarhus University

Aalborg University

Dimensions Citation Indicators

Times Cited: 28

Field Citation Ratio (FCR): 15.57

Relative Citation ratio (RCR): 1.42

Open Access Info

Green, Published