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

Author:

Manning Alisa123,Highland Heather M.45,Gasser Jessica1,Sim Xueling67,Tukiainen Taru189,Fontanillas Pierre110,Grarup Niels11,Rivas Manuel A.12,Mahajan Anubha12,Locke Adam E.6,Cingolani Pablo1314,Pers Tune H.1111516,Viñuela Ana171819,Brown Andrew A.2021,Wu Ying22,Flannick Jason123,Fuchsberger Christian6,Gamazon Eric R.2425,Gaulton Kyle J.1226,Im Hae Kyung24,Teslovich Tanya M.6,Blackwell Thomas W.6,Bork-Jensen Jette11,Burtt Noël P.1,Chen Yuhui12,Green Todd1,Hartl Christopher1,Kang Hyun Min6,Kumar Ashish1227,Ladenvall Claes28,Ma Clement6,Moutsianas Loukas12,Pearson Richard D.12,Perry John R.B.122930,Rayner N. William123132,Robertson Neil R.1231,Scott Laura J.6,van de Bunt Martijn1231,Eriksson Johan G.3334353637,Jula Antti37,Koskinen Seppo37,Lehtimäki Terho38,Palotie Aarno1239,Raitakari Olli T.4041,Jacobs Suzanne B.R.1,Wessel Jennifer4243,Chu Audrey Y.44,Scott Robert A.30,Goodarzi Mark O.4546,Blancher Christine47,Buck Gemma47,Buck David47,Chines Peter S.48,Gabriel Stacey1,Gjesing Anette P.11,Groves Christopher J.31,Hollensted Mette11,Huyghe Jeroen R.6,Jackson Anne U.6,Jun Goo6,Justesen Johanne Marie11,Mangino Massimo17,Murphy Jacquelyn1,Neville Matt31,Onofrio Robert1,Small Kerrin S.17,Stringham Heather M.6,Trakalo Joseph47,Banks Eric1,Carey Jason1,Carneiro Mauricio O.1,DePristo Mark1,Farjoun Yossi1,Fennell Timothy1,Goldstein Jacqueline I.18,Grant George1,Hrabé de Angelis Martin495051,Maguire Jared1,Neale Benjamin M.18,Poplin Ryan1,Purcell Shaun1252,Schwarzmayr Thomas53,Shakir Khalid1,Smith Joshua D.54,Strom Tim M.5355,Wieland Thomas53,Lindstrom Jaana56,Brandslund Ivan5758,Christensen Cramer59,Surdulescu Gabriela L.17,Lakka Timo A.606162,Doney Alex S.F.63,Nilsson Peter64,Wareham Nicholas J.30,Langenberg Claudia30,Varga Tibor V.65,Franks Paul W.656667,Rolandsson Olov67,Rosengren Anders H.28,Farook Vidya S.68,Thameem Farook69,Puppala Sobha68,Kumar Satish68,Lehman Donna M.69,Jenkinson Christopher P.6970,Curran Joanne E.68,Hale Daniel Esten71,Fowler Sharon P.69,Arya Rector71,DeFronzo Ralph A.69,Abboud Hanna E.69,Syvänen Ann-Christine72,Hicks Pamela J.737475,Palmer Nicholette D.737475,Ng Maggie C.Y.7374,Bowden Donald W.737475,Freedman Barry I.76,Esko Tõnu197778,Mägi Reedik78,Milani Lili78,Mihailov Evelin78,Metspalu Andres78,Narisu Narisu48,Kinnunen Leena37,Bonnycastle Lori L.48,Swift Amy48,Pasko Dorota29,Wood Andrew R.29,Fadista João28,Pollin Toni I.79,Barzilai Nir80,Atzmon Gil8081,Glaser Benjamin82,Thorand Barbara5083,Strauch Konstantin8485,Peters Annette508386,Roden Michael8788,Müller-Nurasyid Martina84858689,Liang Liming9091,Kriebel Jennifer508392,Illig Thomas929394,Grallert Harald508392,Gieger Christian84,Meisinger Christa83,Lannfelt Lars95,Musani Solomon K.96,Griswold Michael97,Taylor Herman A.98,Wilson Gregory99,Correa Adolfo98,Oksa Heikki100,Scott William R.101,Afzal Uzma101,Tan Sian-Tsung102103,Loh Marie101104105,Chambers John C.101103106,Sehmi Jobanpreet102103,Kooner Jaspal Singh102,Lehne Benjamin101,Cho Yoon Shin107,Lee Jong-Young108,Han Bok-Ghee109,Käräjämäki Annemari110111,Qi Qibin66112,Qi Lu66113,Huang Jinyan90,Hu Frank B.6690,Melander Olle114,Orho-Melander Marju115,Below Jennifer E.116,Aguilar David117,Wong Tien Yin118119,Liu Jianjun7120,Khor Chiea-Chuen7118119120121,Chia Kee Seng7,Lim Wei Yen7,Cheng Ching-Yu7118119122,Chan Edmund123,Tai E Shyong7123124,Aung Tin118119,Linneberg Allan125126127,Isomaa Bo35128,Meitinger Thomas535586,Tuomi Tiinamaija35129,Hakaste Liisa35,Kravic Jasmina28,Jørgensen Marit E.130,Lauritzen Torsten131,Deloukas Panos32,Stirrups Kathleen E.132133,Owen Katharine R.31134,Farmer Andrew J.135,Frayling Timothy M.29,O'Rahilly Stephen P.136,Walker Mark137,Levy Jonathan C.31,Hodgkiss Dylan17,Hattersley Andrew T.138,Kuulasmaa Teemu139,Stančáková Alena139,Barroso Inês32136,Bharadwaj Dwaipayan140,Chan Juliana141142143,Chandak Giriraj R.144,Daly Mark J.8,Donnelly Peter J.12145,Ebrahim Shah B.146,Elliott Paul101147,Fingerlin Tasha148,Froguel Philippe149,Hu Cheng150,Jia Weiping150,Ma Ronald C.W.141142143,McVean Gilean12,Park Taesung151152,Prabhakaran Dorairaj146,Sandhu Manjinder32153,Scott James102,Sladek Rob14154155,Tandon Nikhil156,Teo Yik Ying7157158,Zeggini Eleftheria32,Watanabe Richard M.159160161,Koistinen Heikki A.37162163,Kesaniemi Y. Antero164,Uusitupa Matti165,Spector Timothy D.17,Salomaa Veikko37,Rauramaa Rainer166,Palmer Colin N.A.167,Prokopenko Inga1231168,Morris Andrew D.169,Bergman Richard N.170,Collins Francis S.48,Lind Lars171,Ingelsson Erik72172,Tuomilehto Jaakko56173174175,Karpe Fredrik31134,Groop Leif28,Jørgensen Torben125176,Hansen Torben11177,Pedersen Oluf11,Kuusisto Johanna139178,Abecasis Gonçalo6,Bell Graeme I.179,Blangero John68,Cox Nancy J.24,Duggirala Ravindranath68,Seielstad Mark180181,Wilson James G.182,Dupuis Josee183184,Ripatti Samuli2039185,Hanis Craig L.116,Florez Jose C.123186,Mohlke Karen L.22,Meigs James B.13187,Laakso Markku139178,Morris Andrew P.1278188,Boehnke Michael6,Altshuler David13923186,McCarthy Mark I.1231134,Gloyn Anna L.1231134,Lindgren Cecilia M.112189

Affiliation:

1. Program in Medical and Population Genetics, Broad Institute, Cambridge, MA

2. Center for Human Genetic Research, Department of Medicine, Massachusetts General Hospital, Boston, MA

3. Department of Medicine, Harvard Medical School, Boston, MA

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. Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC

6. Department of Biostatistics and Center for Statistical Genetics, School of Public Health, University of Michigan, Ann Arbor, MI

7. Saw Swee Hock School of Public Health, National University of Singapore, Singapore

8. Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA

9. Department of Genetics, Harvard Medical School, Boston, MA

10. 23andMe, Mountain View, CA

11. The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

12. Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, U.K.

13. School of Computer Science, McGill University, Montreal, Canada

14. McGill University and Génome Québec Innovation Centre, Montreal, Canada

15. Divisions of Endocrinology and Genetics and Genomics and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA

16. Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark

17. Department of Twin Research & Genetic Epidemiology, King’s College London, London, U.K.

18. Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland

19. Institute of Genetics and Genomics in Geneva, University of Geneva, Geneva, Switzerland

20. Wellcome Trust Sanger Institute, Hinxton, U.K.

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. Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC

23. Department of Molecular Biology, Massachusetts General Hospital, Boston, MA

24. Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL

25. Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands

26. Department of Pediatrics, University of California, San Diego, La Jolla, CA

27. Chronic Disease Epidemiology Unit, Swiss Tropical and Public Health Institute, University of Basel, Basel, Switzerland

28. Diabetes and Endocrinology Unit, Department of Clinical Sciences Malmö, Lund University Diabetes Centre, Malmö, Sweden

29. Genetics of Complex Traits, University of Exeter Medical School, Exeter, U.K.

30. MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, U.K.

31. Oxford Centre for Diabetes, Endocrinology & Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, U.K.

32. Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, U.K.

33. Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland

34. Unit of General Practice, Helsinki University Central Hospital, Helsinki, Finland

35. Folkhälsan Research Center, Helsinki, Finland

36. Vaasa Central Hospital, Vaasa, Finland

37. Department of Health, National Institute for Health and Welfare, Helsinki, Finland

38. Department of Clinical Chemistry, Fimlab Laboratories, University of Tampere School of Medicine, Tampere, Finland

39. Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland

40. Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland

41. Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland

42. Department of Epidemiology, Fairbanks School of Public Health, Indianapolis, IN

43. Department of Medicine, Indiana University School of Medicine, Indianapolis, IN

44. Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA

45. Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA

46. Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA

47. High-Throughput Genomics, Oxford Genomics Centre, Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, U.K.

48. National Human Genome Research Institute, National Institutes of Health, Bethesda, MD

49. Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany

50. German Center for Diabetes Research (DZD), Neuherberg, Germany

51. Institute of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, Freising, Germany

52. Department of Psychiatry, Icahn Institute for Genomics & Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY

53. Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany

54. Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA

55. Institute of Human Genetics, Technische Universität München, Neuherberg, Germany

56. Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland

57. Department of Regional Health Research, University of Southern Denmark, Odense, Denmark

58. Department of Clinical Biochemistry, Vejle Hospital, Vejle, Denmark

59. Department of Internal Medicine and Endocrinology, Vejle Hospital, Vejle, Denmark

60. Department of Physiology, Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland

61. Kuopio Research Institute of Exercise Medicine, Kuopio, Finland

62. Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland

63. Division of Cardiovascular & Diabetes Medicine, Medical Research Institute, Ninewells Hospital and Medical School, Dundee, U.K.

64. Department of Clinical Sciences, Faculty of Medicine, Lund University, Malmö, Sweden

65. Department of Clinical Sciences, Lund University Diabetes Centre, and Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden

66. Department of Nutrition, Harvard School of Public Health, Boston, MA

67. Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden

68. Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX

69. Department of Medicine, The University of Texas Health Science Center, San Antonio, TX

70. Research and Development Service, South Texas Veterans Health Care System, San Antonio, TX

71. Department of Pediatrics, The University of Texas Health Science Center, San Antonio, TX

72. Molecular Medicine and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden

73. Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC

74. Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC

75. Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC

76. Section on Nephrology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC

77. Division of Endocrinology, Boston Children's Hospital, Boston, MA

78. Estonian Genome Center, University of Tartu, Tartu, Estonia

79. Program in Personalized and Genomic Medicine, Department of Medicine, University of Maryland, Baltimore, MD

80. Departments of Medicine and Genetics, Albert Einstein College of Medicine, New York, NY

81. Faculty of Natural Sciences, University of Haifa, Haifa, Israel

82. Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

83. Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany

84. Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany

85. Department of Genetic Epidemiology, Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany

86. Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), Partner Site Munich Heart Alliance, Munich, Germany

87. Institute of Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany

88. German Center for Diabetes Research, Partner Düsseldorf, Germany

89. Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany

90. Department of Epidemiology, Harvard School of Public Health, Boston, MA

91. Department of Biostatistics, Harvard School of Public Health, Boston, MA

92. Research Unit Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany

93. Hannover Unified Biobank, Hannover Medical School, Hannover, Germany

94. Institute of Human Genetics, Hannover Medical School, Hannover, Germany

95. Geriatrics, Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden

96. Jackson Heart Study, University of Mississippi Medical Center, Jackson, MS

97. Center of Biostatistics and Bioinformatics, University of Mississippi Medical Center, Jackson, MS

98. Department of Medicine, University of Mississippi Medical Center, Jackson, MS

99. College of Public Services, Jackson State University, Jackson, MS

100. Pirkanmaa Hospital District, Tampere, Finland

101. Department of Epidemiology and Biostatistics, Imperial College London, London, U.K.

102. Cardiovascular Sciences, National Heart and Lung Institute, Imperial College London, London, U.K.

103. Department of Cardiology, Ealing Hospital NHS Trust, Southall, U.K.

104. Institute of Health Sciences, University of Oulu, Oulu, Finland

105. Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research (A*STAR), Singapore

106. Imperial College Healthcare NHS Trust, Imperial College London, London, U.K.

107. Department of Biomedical Science, Hallym University, Chuncheon, Republic of Korea

108. Ministry of Health and Welfare, Seoul, Republic of Korea

109. Center for Genome Science, Korea National Research Institute of Health, Chungcheongbuk-do, Republic of Korea

110. Vaasa Health Care Center, Vaasa, Finland

111. Department of Primary Health Care, Vaasa Central Hospital, Vaasa, Finland

112. Department of Epidemiology and Population Health, Albert Einstein College of Medicine, New York, NY

113. Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA

114. Hypertension and Cardiovascular Disease, Department of Clinical Sciences, Lund University, Malmö, Sweden

115. Diabetes and Cardiovascular Disease–Genetic Epidemiology, Department of Clinical Sciences, Lund University, Malmö, Sweden

116. Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX

117. Cardiovascular Division, Baylor College of Medicine, Houston, TX

118. Singapore Eye Research Institute, Singapore National Eye Centre, Singapore

119. Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

120. Division of Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore

121. Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

122. Office of Clinical Sciences, Centre for Quantitative Medicine, Duke-NUS Graduate Medical School Singapore, Singapore

123. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

124. Cardiovascular & Metabolic Disorders Program, Duke-NUS Graduate Medical School Singapore, Singapore

125. Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark

126. Department of Clinical Experimental Research, Rigshospitalet, Glostrup, Denmark

127. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

128. Department of Social Services and Health Care, Jakobstad, Finland

129. Department of Endocrinology, Helsinki University Central Hospital, Helsinki, Finland

130. Steno Diabetes Center, Gentofte, Denmark

131. Section of General Practice, Department of Public Health, Aarhus University, Aarhus, Denmark

132. William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, U.K.

133. Department of Haematology, University of Cambridge, Cambridge, U.K.

134. Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, U.K.

135. Department of Primary Care Health Sciences, University of Oxford, Oxford, U.K.

136. Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, U.K.

137. Institute of Cellular Medicine, University of Newcastle, Newcastle, U.K.

138. University of Exeter Medical School, Exeter, U.K.

139. Internal Medicine, Institute of Clinical Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland

140. Functional Genomics Unit, CSIR-Institute of Genomics & Integrative Biology, New Delhi, India

141. Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China

142. Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China

143. Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, China

144. CSIR-Centre for Cellular & Molecular Biology, Hyderabad, India

145. Department of Statistics, University of Oxford, Oxford, U.K.

146. Centre for Chronic Disease Control, New Delhi, India

147. MRC-PHE Centre for Environment & Health, Imperial College London, London, U.K.

148. Department of Epidemiology, Colorado School of Public Health, University of Colorado, Aurora, CO

149. Genomics and Molecular Physiology, CNRS Institut de Biologie de Lille, Lille, France

150. Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China

151. Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul, Republic of Korea

152. Department of Statistics, Seoul National University, Seoul, Republic of Korea

153. Institute of Public Health, Department of Public Health and Primary Care, University of Cambridge, Cambridge, U.K.

154. Department of Human Genetics, McGill University, Montreal, Canada

155. Division of Endocrinology and Metabolism, Department of Medicine, McGill University, Montreal, Canada

156. Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, New Delhi, India

157. Life Sciences Institute, National University of Singapore, Singapore

158. Department of Statistics and Applied Probability, National University of Singapore, Singapore

159. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA

160. Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA

161. Diabetes & Obesity Research Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA

162. Department of Medicine and Abdominal Center, Endocrinology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland

163. Minerva Foundation Institute for Medical Research, Helsinki, Finland

164. Institute of Clinical Medicine, Faculty of Medicine, University of Oulu, Oulu, Finland

165. Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland

166. Foundation for Research in Health Exercise and Nutrition, Kuopio Research Institute of Exercise Medicine, Kuopio, Finland

167. Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Medical Research Institute, Ninewells Hospital and Medical School, Dundee, U.K.

168. Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, U.K.

169. Division for Molecular Medicine, Clinical Research Centre, Ninewells Hospital and Medical School, Dundee, U.K.

170. Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA

171. Department of Medical Sciences, Uppsala University, Uppsala, Sweden

172. Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA

173. Center for Vascular Prevention, Danube University Krems, Krems, Austria

174. Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia

175. Dasman Diabetes Institute, Dasman, Kuwait

176. Faculty of Medicine, University of Aalborg, Aalborg, Denmark

177. Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark

178. Kuopio University Hospital, Kuopio, Finland

179. Departments of Medicine and Human Genetics, The University of Chicago, Chicago, IL

180. Department of Laboratory Medicine, Institute for Human Genetics, University of California, San Francisco, San Francisco, CA

181. Blood Systems Research Institute, San Francisco, CA

182. Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS

183. Department of Biostatistics, Boston University School of Public Health, Boston, MA

184. Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, MA

185. Hjelt Institute, University of Helsinki, Helsinki, Finland

186. Diabetes Research Center (Diabetes Unit), Department of Medicine, Massachusetts General Hospital, Boston, MA

187. Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA

188. Department of Biostatistics, University of Liverpool, Liverpool, U.K.

189. Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, U.K.

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.

Funder

American Diabetes Association

National Cancer Institute

National Heart, Lung, and Blood Institute

National Institute on Aging

National Institutes of Diabetes and Digestive and Kidney Diseases

National Institute of General Medical Sciences

National Institutes of Health

National Institutes of Health Office of the Director

National Institute of Mental Health

Wellcome Trust

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

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