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Diabetes. 2017 Jul;66(7):2019-2032. doi: 10.2337/db16-1329. Epub 2017 Mar 24.

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

Manning A1,2,3, Highland HM4,5, Gasser J1, Sim X6,7, Tukiainen T1,8,9, Fontanillas P1,10, Grarup N11, Rivas MA12, Mahajan A12, Locke AE6, Cingolani P13,14, Pers TH1,11,15,16, Viñuela A17,18,19, Brown AA20,21, Wu Y22, Flannick J1,23, Fuchsberger C6, Gamazon ER24,25, Gaulton KJ12,26, Im HK24, Teslovich TM6, Blackwell TW6, Bork-Jensen J11, Burtt NP1, Chen Y12, Green T1, Hartl C1, Kang HM6, Kumar A12,27, Ladenvall C28, Ma C6, Moutsianas L12, Pearson RD12, Perry JRB12,29,30, Rayner NW12,31,32, Robertson NR12,31, Scott LJ6, van de Bunt M12,31, Eriksson JG33,34,35,36,37, Jula A37, Koskinen S37, Lehtimäki T38, Palotie A1,2,39, Raitakari OT40,41, Jacobs SBR1, Wessel J42,43, Chu AY44, Scott RA30, Goodarzi MO45,46, Blancher C47, Buck G47, Buck D47, Chines PS48, Gabriel S1, Gjesing AP11, Groves CJ31, Hollensted M11, Huyghe JR6, Jackson AU6, Jun G6, Justesen JM11, Mangino M17, Murphy J1, Neville M31, Onofrio R1, Small KS17, Stringham HM6, Trakalo J47, Banks E1, Carey J1, Carneiro MO1, DePristo M1, Farjoun Y1, Fennell T1, Goldstein JI1,8, Grant G1, Hrabé de Angelis M49,50,51, Maguire J1, Neale BM1,8, Poplin R1, Purcell S1,2,52, Schwarzmayr T53, Shakir K1, Smith JD54, Strom TM53,55, Wieland T53, Lindstrom J56, Brandslund I57,58, Christensen C59, Surdulescu GL17, Lakka TA60,61,62, Doney ASF63, Nilsson P64, Wareham NJ30, Langenberg C30, Varga TV65, Franks PW65,66,67, Rolandsson O67, Rosengren AH28, Farook VS68, Thameem F69, Puppala S68, Kumar S68, Lehman DM69, Jenkinson CP69,70, Curran JE68, Hale DE71, Fowler SP69, Arya R71, DeFronzo RA69, Abboud HE69, Syvänen AC72, Hicks PJ73,74,75, Palmer ND73,74,75, Ng MCY73,74, Bowden DW73,74,75, Freedman BI76, Esko T1,9,77,78, Mägi R78, Milani L78, Mihailov E78, Metspalu A78, Narisu N48, Kinnunen L37, Bonnycastle LL48, Swift A48, Pasko D29, Wood AR29, Fadista J28, Pollin TI79, Barzilai N80, Atzmon G80,81, Glaser B82, Thorand B50,83, Strauch K84,85, Peters A50,83,86, Roden M87,88, Müller-Nurasyid M84,85,86,89, Liang L90,91, Kriebel J50,83,92, Illig T92,93,94, Grallert H50,83,92, Gieger C84, Meisinger C83, Lannfelt L95, Musani SK96, Griswold M97, Taylor HA Jr98, Wilson G Sr99, Correa A98, Oksa H100, Scott WR101, Afzal U101, Tan ST102,103, Loh M101,104,105, Chambers JC101,103,106, Sehmi J102,103, Kooner JS102, Lehne B101, Cho YS107, Lee JY108, Han BG109, Käräjämäki A110,111, Qi Q66,112, Qi L66,113, Huang J90, Hu FB66,90, Melander O114, Orho-Melander M115, Below JE116, Aguilar D117, Wong TY118,119, Liu J7,120, Khor CC7,118,119,120,121, Chia KS7, Lim WY7, Cheng CY7,118,119,122, Chan E123, Tai ES7,123,124, Aung T118,119, Linneberg A125,126,127, Isomaa B35,128, Meitinger T53,55,86, Tuomi T35,129, Hakaste L35, Kravic J28, Jørgensen ME130, Lauritzen T131, Deloukas P32, Stirrups KE132,133, Owen KR31,134, Farmer AJ135, Frayling TM29, O'Rahilly SP136, Walker M137, Levy JC31, Hodgkiss D17, Hattersley AT138, Kuulasmaa T139, Stančáková A139, Barroso I32,136, Bharadwaj D140, Chan J141,142,143, Chandak GR144, Daly MJ8, Donnelly PJ12,145, Ebrahim SB146, Elliott P101,147, Fingerlin T148, Froguel P149, Hu C150, Jia W150, Ma RCW141,142,143, McVean G12, Park T151,152, Prabhakaran D146, Sandhu M32,153, Scott J102, Sladek R14,154,155, Tandon N156, Teo YY7,157,158, Zeggini E32, Watanabe RM159,160,161, Koistinen HA37,162,163, Kesaniemi YA164, Uusitupa M165, Spector TD17, Salomaa V37, Rauramaa R166, Palmer CNA167, Prokopenko I12,31,168, Morris AD169, Bergman RN170, Collins FS48, Lind L171, Ingelsson E72,172, Tuomilehto J56,173,174,175, Karpe F31,134, Groop L28, Jørgensen T125,176, Hansen T11,177, Pedersen O11, Kuusisto J139,178, Abecasis G6, Bell GI179, Blangero J68, Cox NJ24, Duggirala R68, Seielstad M180,181, Wilson JG182, Dupuis J183,184, Ripatti S20,39,185, Hanis CL116, Florez JC1,2,3,186, Mohlke KL22, Meigs JB1,3,187, Laakso M139,178, Morris AP12,78,188, Boehnke M6, Altshuler D1,3,9,23,186,189, McCarthy MI12,31,134, Gloyn AL12,31,134, Lindgren CM1,12,190.

Author information

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.

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.

PMID:
28341696
PMCID:
PMC5482074
DOI:
10.2337/db16-1329
[Indexed for MEDLINE]
Free PMC Article

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