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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- Cecilia M. Lindgren1,12,190
- 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 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA
- 190 Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, U.K.
- Corresponding authors: Anna L. Gloyn, anna.gloyn{at}drl.ox.ac.uk, and Cecilia M. Lindgren, celi{at}well.ox.ac.uk.
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.

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
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db16-1329/-/DC1.
- Received November 11, 2016.
- Accepted March 13, 2017.
- © 2017 by the American Diabetes Association.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.