Genetics/Genomes/Proteomics/Metabolomics

A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk

  1. Alisa Manning1,2,3,
  2. Heather M. Highland4,5,
  3. Jessica Gasser1,
  4. Xueling Sim6,7,
  5. Taru Tukiainen1,8,9,
  6. Pierre Fontanillas1,10,
  7. Niels Grarup11,
  8. Manuel A. Rivas12,
  9. Anubha Mahajan12,
  10. Adam E. Locke6,
  11. Pablo Cingolani13,14,
  12. Tune H. Pers1,11,15,16,
  13. Ana Viñuela17,18,19,
  14. Andrew A. Brown20,21,
  15. Ying Wu22,
  16. Jason Flannick1,23,
  17. Christian Fuchsberger6,
  18. Eric R. Gamazon24,25,
  19. Kyle J. Gaulton12,26,
  20. Hae Kyung Im24,
  21. Tanya M. Teslovich6,
  22. Thomas W. Blackwell6,
  23. Jette Bork-Jensen11,
  24. Noël P. Burtt1,
  25. Yuhui Chen12,
  26. Todd Green1,
  27. Christopher Hartl1,
  28. Hyun Min Kang6,
  29. Ashish Kumar12,27,
  30. Claes Ladenvall28,
  31. Clement Ma6,
  32. Loukas Moutsianas12,
  33. Richard D. Pearson12,
  34. John R.B. Perry12,29,30,
  35. N. William Rayner12,31,32,
  36. Neil R. Robertson12,31,
  37. Laura J. Scott6,
  38. Martijn van de Bunt12,31,
  39. Johan G. Eriksson33,34,35,36,37,
  40. Antti Jula37,
  41. Seppo Koskinen37,
  42. Terho Lehtimäki38,
  43. Aarno Palotie1,2,39,
  44. Olli T. Raitakari40,41,
  45. Suzanne B.R. Jacobs1,
  46. Jennifer Wessel42,43,
  47. Audrey Y. Chu44,
  48. Robert A. Scott30,
  49. Mark O. Goodarzi45,46,
  50. Christine Blancher47,
  51. Gemma Buck47,
  52. David Buck47,
  53. Peter S. Chines48,
  54. Stacey Gabriel1,
  55. Anette P. Gjesing11,
  56. Christopher J. Groves31,
  57. Mette Hollensted11,
  58. Jeroen R. Huyghe6,
  59. Anne U. Jackson6,
  60. Goo Jun6,
  61. Johanne Marie Justesen11,
  62. Massimo Mangino17,
  63. Jacquelyn Murphy1,
  64. Matt Neville31,
  65. Robert Onofrio1,
  66. Kerrin S. Small17,
  67. Heather M. Stringham6,
  68. Joseph Trakalo47,
  69. Eric Banks1,
  70. Jason Carey1,
  71. Mauricio O. Carneiro1,
  72. Mark DePristo1,
  73. Yossi Farjoun1,
  74. Timothy Fennell1,
  75. Jacqueline I. Goldstein1,8,
  76. George Grant1,
  77. Martin Hrabé de Angelis49,50,51,
  78. Jared Maguire1,
  79. Benjamin M. Neale1,8,
  80. Ryan Poplin1,
  81. Shaun Purcell1,2,52,
  82. Thomas Schwarzmayr53,
  83. Khalid Shakir1,
  84. Joshua D. Smith54,
  85. Tim M. Strom53,55,
  86. Thomas Wieland53,
  87. Jaana Lindstrom56,
  88. Ivan Brandslund57,58,
  89. Cramer Christensen59,
  90. Gabriela L. Surdulescu17,
  91. Timo A. Lakka60,61,62,
  92. Alex S.F. Doney63,
  93. Peter Nilsson64,
  94. Nicholas J. Wareham30,
  95. Claudia Langenberg30,
  96. Tibor V. Varga65,
  97. Paul W. Franks65,66,67,
  98. Olov Rolandsson67,
  99. Anders H. Rosengren28,
  100. Vidya S. Farook68,
  101. Farook Thameem69,
  102. Sobha Puppala68,
  103. Satish Kumar68,
  104. Donna M. Lehman69,
  105. Christopher P. Jenkinson69,70,
  106. Joanne E. Curran68,
  107. Daniel Esten Hale71,
  108. Sharon P. Fowler69,
  109. Rector Arya71,
  110. Ralph A. DeFronzo69,
  111. Hanna E. Abboud69,
  112. Ann-Christine Syvänen72,
  113. Pamela J. Hicks73,74,75,
  114. Nicholette D. Palmer73,74,75,
  115. Maggie C.Y. Ng73,74,
  116. Donald W. Bowden73,74,75,
  117. Barry I. Freedman76,
  118. Tõnu Esko1,9,77,78,
  119. Reedik Mägi78,
  120. Lili Milani78,
  121. Evelin Mihailov78,
  122. Andres Metspalu78,
  123. Narisu Narisu48,
  124. Leena Kinnunen37,
  125. Lori L. Bonnycastle48,
  126. Amy Swift48,
  127. Dorota Pasko29,
  128. Andrew R. Wood29,
  129. João Fadista28,
  130. Toni I. Pollin79,
  131. Nir Barzilai80,
  132. Gil Atzmon80,81,
  133. Benjamin Glaser82,
  134. Barbara Thorand50,83,
  135. Konstantin Strauch84,85,
  136. Annette Peters50,83,86,
  137. Michael Roden87,88,
  138. Martina Müller-Nurasyid84,85,86,89,
  139. Liming Liang90,91,
  140. Jennifer Kriebel50,83,92,
  141. Thomas Illig92,93,94,
  142. Harald Grallert50,83,92,
  143. Christian Gieger84,
  144. Christa Meisinger83,
  145. Lars Lannfelt95,
  146. Solomon K. Musani96,
  147. Michael Griswold97,
  148. Herman A. Taylor Jr.98,
  149. Gregory Wilson Sr.99,
  150. Adolfo Correa98,
  151. Heikki Oksa100,
  152. William R. Scott101,
  153. Uzma Afzal101,
  154. Sian-Tsung Tan102,103,
  155. Marie Loh101,104,105,
  156. John C. Chambers101,103,106,
  157. Jobanpreet Sehmi102,103,
  158. Jaspal Singh Kooner102,
  159. Benjamin Lehne101,
  160. Yoon Shin Cho107,
  161. Jong-Young Lee108,
  162. Bok-Ghee Han109,
  163. Annemari Käräjämäki110,111,
  164. Qibin Qi66,112,
  165. Lu Qi66,113,
  166. Jinyan Huang90,
  167. Frank B. Hu66,90,
  168. Olle Melander114,
  169. Marju Orho-Melander115,
  170. Jennifer E. Below116,
  171. David Aguilar117,
  172. Tien Yin Wong118,119,
  173. Jianjun Liu7,120,
  174. Chiea-Chuen Khor7,118,119,120,121,
  175. Kee Seng Chia7,
  176. Wei Yen Lim7,
  177. Ching-Yu Cheng7,118,119,122,
  178. Edmund Chan123,
  179. E Shyong Tai7,123,124,
  180. Tin Aung118,119,
  181. Allan Linneberg125,126,127,
  182. Bo Isomaa35,128,
  183. Thomas Meitinger53,55,86,
  184. Tiinamaija Tuomi35,129,
  185. Liisa Hakaste35,
  186. Jasmina Kravic28,
  187. Marit E. Jørgensen130,
  188. Torsten Lauritzen131,
  189. Panos Deloukas32,
  190. Kathleen E. Stirrups132,133,
  191. Katharine R. Owen31,134,
  192. Andrew J. Farmer135,
  193. Timothy M. Frayling29,
  194. Stephen P. O'Rahilly136,
  195. Mark Walker137,
  196. Jonathan C. Levy31,
  197. Dylan Hodgkiss17,
  198. Andrew T. Hattersley138,
  199. Teemu Kuulasmaa139,
  200. Alena Stančáková139,
  201. Inês Barroso32,136,
  202. Dwaipayan Bharadwaj140,
  203. Juliana Chan141,142,143,
  204. Giriraj R. Chandak144,
  205. Mark J. Daly8,
  206. Peter J. Donnelly12,145,
  207. Shah B. Ebrahim146,
  208. Paul Elliott101,147,
  209. Tasha Fingerlin148,
  210. Philippe Froguel149,
  211. Cheng Hu150,
  212. Weiping Jia150,
  213. Ronald C.W. Ma141,142,143,
  214. Gilean McVean12,
  215. Taesung Park151,152,
  216. Dorairaj Prabhakaran146,
  217. Manjinder Sandhu32,153,
  218. James Scott102,
  219. Rob Sladek14,154,155,
  220. Nikhil Tandon156,
  221. Yik Ying Teo7,157,158,
  222. Eleftheria Zeggini32,
  223. Richard M. Watanabe159,160,161,
  224. Heikki A. Koistinen37,162,163,
  225. Y. Antero Kesaniemi164,
  226. Matti Uusitupa165,
  227. Timothy D. Spector17,
  228. Veikko Salomaa37,
  229. Rainer Rauramaa166,
  230. Colin N.A. Palmer167,
  231. Inga Prokopenko12,31,168,
  232. Andrew D. Morris169,
  233. Richard N. Bergman170,
  234. Francis S. Collins48,
  235. Lars Lind171,
  236. Erik Ingelsson72,172,
  237. Jaakko Tuomilehto56,173,174,175,
  238. Fredrik Karpe31,134,
  239. Leif Groop28,
  240. Torben Jørgensen125,176,
  241. Torben Hansen11,177,
  242. Oluf Pedersen11,
  243. Johanna Kuusisto139,178,
  244. Gonçalo Abecasis6,
  245. Graeme I. Bell179,
  246. John Blangero68,
  247. Nancy J. Cox24,
  248. Ravindranath Duggirala68,
  249. Mark Seielstad180,181,
  250. James G. Wilson182,
  251. Josee Dupuis183,184,
  252. Samuli Ripatti20,39,185,
  253. Craig L. Hanis116,
  254. Jose C. Florez1,2,3,186,
  255. Karen L. Mohlke22,
  256. James B. Meigs1,3,187,
  257. Markku Laakso139,178,
  258. Andrew P. Morris12,78,188,
  259. Michael Boehnke6,
  260. David Altshuler1,3,9,23,186,189,
  261. Mark I. McCarthy12,31,134,
  262. Anna L. Gloyn12,31,134 and
  263. Cecilia M. Lindgren1,12,190
  1. 1 Program in Medical and Population Genetics, Broad Institute, Cambridge, MA
  2. 2 Center for Human Genetic Research, Department of Medicine, Massachusetts General Hospital, Boston, MA
  3. 3 Department of Medicine, Harvard Medical School, Boston, MA
  4. 4 Human Genetics Center, The University of Texas MD Anderson Cancer Center and The University of Texas Health Science Center at Houston Graduate School of Biomedical Sciences, Houston, TX
  5. 5 Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC
  6. 6 Department of Biostatistics and Center for Statistical Genetics, School of Public Health, University of Michigan, Ann Arbor, MI
  7. 7 Saw Swee Hock School of Public Health, National University of Singapore, Singapore
  8. 8 Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA
  9. 9 Department of Genetics, Harvard Medical School, Boston, MA
  10. 10 23andMe, Mountain View, CA
  11. 11 The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  12. 12 Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, U.K.
  13. 13 School of Computer Science, McGill University, Montreal, Canada
  14. 14 McGill University and Génome Québec Innovation Centre, Montreal, Canada
  15. 15 Divisions of Endocrinology and Genetics and Genomics and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA
  16. 16 Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
  17. 17 Department of Twin Research & Genetic Epidemiology, King’s College London, London, U.K.
  18. 18 Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
  19. 19 Institute of Genetics and Genomics in Geneva, University of Geneva, Geneva, Switzerland
  20. 20 Wellcome Trust Sanger Institute, Hinxton, U.K.
  21. 21 Norwegian Centre for Mental Disorders Research and KG Jebsen Center for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
  22. 22 Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC
  23. 23 Department of Molecular Biology, Massachusetts General Hospital, Boston, MA
  24. 24 Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL
  25. 25 Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
  26. 26 Department of Pediatrics, University of California, San Diego, La Jolla, CA
  27. 27 Chronic Disease Epidemiology Unit, Swiss Tropical and Public Health Institute, University of Basel, Basel, Switzerland
  28. 28 Diabetes and Endocrinology Unit, Department of Clinical Sciences Malmö, Lund University Diabetes Centre, Malmö, Sweden
  29. 29 Genetics of Complex Traits, University of Exeter Medical School, Exeter, U.K.
  30. 30 MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, U.K.
  31. 31 Oxford Centre for Diabetes, Endocrinology & Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, U.K.
  32. 32 Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, U.K.
  33. 33 Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland
  34. 34 Unit of General Practice, Helsinki University Central Hospital, Helsinki, Finland
  35. 35 Folkhälsan Research Center, Helsinki, Finland
  36. 36 Vaasa Central Hospital, Vaasa, Finland
  37. 37 Department of Health, National Institute for Health and Welfare, Helsinki, Finland
  38. 38 Department of Clinical Chemistry, Fimlab Laboratories, University of Tampere School of Medicine, Tampere, Finland
  39. 39 Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
  40. 40 Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
  41. 41 Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland
  42. 42 Department of Epidemiology, Fairbanks School of Public Health, Indianapolis, IN
  43. 43 Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
  44. 44 Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA
  45. 45 Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA
  46. 46 Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA
  47. 47 High-Throughput Genomics, Oxford Genomics Centre, Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, U.K.
  48. 48 National Human Genome Research Institute, National Institutes of Health, Bethesda, MD
  49. 49 Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
  50. 50 German Center for Diabetes Research (DZD), Neuherberg, Germany
  51. 51 Institute of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, Freising, Germany
  52. 52 Department of Psychiatry, Icahn Institute for Genomics & Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY
  53. 53 Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
  54. 54 Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA
  55. 55 Institute of Human Genetics, Technische Universität München, Neuherberg, Germany
  56. 56 Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland
  57. 57 Department of Regional Health Research, University of Southern Denmark, Odense, Denmark
  58. 58 Department of Clinical Biochemistry, Vejle Hospital, Vejle, Denmark
  59. 59 Department of Internal Medicine and Endocrinology, Vejle Hospital, Vejle, Denmark
  60. 60 Department of Physiology, Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
  61. 61 Kuopio Research Institute of Exercise Medicine, Kuopio, Finland
  62. 62 Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland
  63. 63 Division of Cardiovascular & Diabetes Medicine, Medical Research Institute, Ninewells Hospital and Medical School, Dundee, U.K.
  64. 64 Department of Clinical Sciences, Faculty of Medicine, Lund University, Malmö, Sweden
  65. 65 Department of Clinical Sciences, Lund University Diabetes Centre, and Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden
  66. 66 Department of Nutrition, Harvard School of Public Health, Boston, MA
  67. 67 Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
  68. 68 Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX
  69. 69 Department of Medicine, The University of Texas Health Science Center, San Antonio, TX
  70. 70 Research and Development Service, South Texas Veterans Health Care System, San Antonio, TX
  71. 71 Department of Pediatrics, The University of Texas Health Science Center, San Antonio, TX
  72. 72 Molecular Medicine and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
  73. 73 Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC
  74. 74 Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC
  75. 75 Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC
  76. 76 Section on Nephrology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC
  77. 77 Division of Endocrinology, Boston Children's Hospital, Boston, MA
  78. 78 Estonian Genome Center, University of Tartu, Tartu, Estonia
  79. 79 Program in Personalized and Genomic Medicine, Department of Medicine, University of Maryland, Baltimore, MD
  80. 80 Departments of Medicine and Genetics, Albert Einstein College of Medicine, New York, NY
  81. 81 Faculty of Natural Sciences, University of Haifa, Haifa, Israel
  82. 82 Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
  83. 83 Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
  84. 84 Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
  85. 85 Department of Genetic Epidemiology, Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany
  86. 86 Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
  87. 87 Institute of Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
  88. 88 German Center for Diabetes Research, Partner Düsseldorf, Germany
  89. 89 Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany
  90. 90 Department of Epidemiology, Harvard School of Public Health, Boston, MA
  91. 91 Department of Biostatistics, Harvard School of Public Health, Boston, MA
  92. 92 Research Unit Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
  93. 93 Hannover Unified Biobank, Hannover Medical School, Hannover, Germany
  94. 94 Institute of Human Genetics, Hannover Medical School, Hannover, Germany
  95. 95 Geriatrics, Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden
  96. 96 Jackson Heart Study, University of Mississippi Medical Center, Jackson, MS
  97. 97 Center of Biostatistics and Bioinformatics, University of Mississippi Medical Center, Jackson, MS
  98. 98 Department of Medicine, University of Mississippi Medical Center, Jackson, MS
  99. 99 College of Public Services, Jackson State University, Jackson, MS
  100. 100 Pirkanmaa Hospital District, Tampere, Finland
  101. 101 Department of Epidemiology and Biostatistics, Imperial College London, London, U.K.
  102. 102 Cardiovascular Sciences, National Heart and Lung Institute, Imperial College London, London, U.K.
  103. 103 Department of Cardiology, Ealing Hospital NHS Trust, Southall, U.K.
  104. 104 Institute of Health Sciences, University of Oulu, Oulu, Finland
  105. 105 Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research (A*STAR), Singapore
  106. 106 Imperial College Healthcare NHS Trust, Imperial College London, London, U.K.
  107. 107 Department of Biomedical Science, Hallym University, Chuncheon, Republic of Korea
  108. 108 Ministry of Health and Welfare, Seoul, Republic of Korea
  109. 109 Center for Genome Science, Korea National Research Institute of Health, Chungcheongbuk-do, Republic of Korea
  110. 110 Vaasa Health Care Center, Vaasa, Finland
  111. 111 Department of Primary Health Care, Vaasa Central Hospital, Vaasa, Finland
  112. 112 Department of Epidemiology and Population Health, Albert Einstein College of Medicine, New York, NY
  113. 113 Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
  114. 114 Hypertension and Cardiovascular Disease, Department of Clinical Sciences, Lund University, Malmö, Sweden
  115. 115 Diabetes and Cardiovascular Disease–Genetic Epidemiology, Department of Clinical Sciences, Lund University, Malmö, Sweden
  116. 116 Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX
  117. 117 Cardiovascular Division, Baylor College of Medicine, Houston, TX
  118. 118 Singapore Eye Research Institute, Singapore National Eye Centre, Singapore
  119. 119 Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
  120. 120 Division of Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore
  121. 121 Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
  122. 122 Office of Clinical Sciences, Centre for Quantitative Medicine, Duke-NUS Graduate Medical School Singapore, Singapore
  123. 123 Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
  124. 124 Cardiovascular & Metabolic Disorders Program, Duke-NUS Graduate Medical School Singapore, Singapore
  125. 125 Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark
  126. 126 Department of Clinical Experimental Research, Rigshospitalet, Glostrup, Denmark
  127. 127 Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  128. 128 Department of Social Services and Health Care, Jakobstad, Finland
  129. 129 Department of Endocrinology, Helsinki University Central Hospital, Helsinki, Finland
  130. 130 Steno Diabetes Center, Gentofte, Denmark
  131. 131 Section of General Practice, Department of Public Health, Aarhus University, Aarhus, Denmark
  132. 132 William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, U.K.
  133. 133 Department of Haematology, University of Cambridge, Cambridge, U.K.
  134. 134 Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, U.K.
  135. 135 Department of Primary Care Health Sciences, University of Oxford, Oxford, U.K.
  136. 136 Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, U.K.
  137. 137 Institute of Cellular Medicine, University of Newcastle, Newcastle, U.K.
  138. 138 University of Exeter Medical School, Exeter, U.K.
  139. 139 Internal Medicine, Institute of Clinical Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
  140. 140 Functional Genomics Unit, CSIR-Institute of Genomics & Integrative Biology, New Delhi, India
  141. 141 Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
  142. 142 Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
  143. 143 Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, China
  144. 144 CSIR-Centre for Cellular & Molecular Biology, Hyderabad, India
  145. 145 Department of Statistics, University of Oxford, Oxford, U.K.
  146. 146 Centre for Chronic Disease Control, New Delhi, India
  147. 147 MRC-PHE Centre for Environment & Health, Imperial College London, London, U.K.
  148. 148 Department of Epidemiology, Colorado School of Public Health, University of Colorado, Aurora, CO
  149. 149 Genomics and Molecular Physiology, CNRS Institut de Biologie de Lille, Lille, France
  150. 150 Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
  151. 151 Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul, Republic of Korea
  152. 152 Department of Statistics, Seoul National University, Seoul, Republic of Korea
  153. 153 Institute of Public Health, Department of Public Health and Primary Care, University of Cambridge, Cambridge, U.K.
  154. 154 Department of Human Genetics, McGill University, Montreal, Canada
  155. 155 Division of Endocrinology and Metabolism, Department of Medicine, McGill University, Montreal, Canada
  156. 156 Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, New Delhi, India
  157. 157 Life Sciences Institute, National University of Singapore, Singapore
  158. 158 Department of Statistics and Applied Probability, National University of Singapore, Singapore
  159. 159 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA
  160. 160 Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA
  161. 161 Diabetes & Obesity Research Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA
  162. 162 Department of Medicine and Abdominal Center, Endocrinology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
  163. 163 Minerva Foundation Institute for Medical Research, Helsinki, Finland
  164. 164 Institute of Clinical Medicine, Faculty of Medicine, University of Oulu, Oulu, Finland
  165. 165 Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
  166. 166 Foundation for Research in Health Exercise and Nutrition, Kuopio Research Institute of Exercise Medicine, Kuopio, Finland
  167. 167 Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Medical Research Institute, Ninewells Hospital and Medical School, Dundee, U.K.
  168. 168 Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, U.K.
  169. 169 Division for Molecular Medicine, Clinical Research Centre, Ninewells Hospital and Medical School, Dundee, U.K.
  170. 170 Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA
  171. 171 Department of Medical Sciences, Uppsala University, Uppsala, Sweden
  172. 172 Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA
  173. 173 Center for Vascular Prevention, Danube University Krems, Krems, Austria
  174. 174 Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia
  175. 175 Dasman Diabetes Institute, Dasman, Kuwait
  176. 176 Faculty of Medicine, University of Aalborg, Aalborg, Denmark
  177. 177 Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
  178. 178 Kuopio University Hospital, Kuopio, Finland
  179. 179 Departments of Medicine and Human Genetics, The University of Chicago, Chicago, IL
  180. 180 Department of Laboratory Medicine, Institute for Human Genetics, University of California, San Francisco, San Francisco, CA
  181. 181 Blood Systems Research Institute, San Francisco, CA
  182. 182 Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS
  183. 183 Department of Biostatistics, Boston University School of Public Health, Boston, MA
  184. 184 Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, MA
  185. 185 Hjelt Institute, University of Helsinki, Helsinki, Finland
  186. 186 Diabetes Research Center (Diabetes Unit), Department of Medicine, Massachusetts General Hospital, Boston, MA
  187. 187 Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA
  188. 188 Department of Biostatistics, University of Liverpool, Liverpool, U.K.
  189. 189 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA
  190. 190 Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, U.K.
  1. Corresponding authors: Anna L. Gloyn, anna.gloyn{at}drl.ox.ac.uk, and Cecilia M. Lindgren, celi{at}well.ox.ac.uk.

  1. A.L.G. and C.M.L. jointly directed this research. A.Man., H.M.H., J.G., X.S., T.Tuk., and P.Fo. contributed equally to this work.

Diabetes 2017 Jul; 66(7): 2019-2032. https://doi.org/10.2337/db16-1329

Abstract

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.

Footnotes

  • Received November 11, 2016.
  • Accepted March 13, 2017.
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A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk
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Diabetes Jul 2017, 66 (7) 2019-2032; DOI: 10.2337/db16-1329
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