A Low-Frequency Inactivating <i>AKT2</i> Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk
Alisa K. Manning(Broad Institute), Heather M. Highland(University of North Carolina at Chapel Hill), Jessica A. Gasser(Broad Institute), Xueling Sim(National University of Singapore), Taru Tukiainen(Broad Institute), Pierre Fontanillas(Broad Institute), Niels Grarup(University of Copenhagen), Manuel A. Rivas(Centre for Human Genetics), Anubha Mahajan(Centre for Human Genetics), Adam E. Locke(University of Michigan), Pablo Cingolani(McGill University and Génome Québec Innovation Centre), Tune H. Pers(Statens Serum Institut), Ana Viñuela(University of Geneva), Andrew Brown(Oslo University Hospital), Ying Wu(University of North Carolina at Chapel Hill), Jason Flannick(Broad Institute), Christian Fuchsberger(University of Michigan), Eric R. Gamazon(Amsterdam UMC Location University of Amsterdam), Kyle J. Gaulton(Centre for Human Genetics), Hae Kyung Im(University of Chicago), Tanya M. Teslovich(University of Michigan), Thomas W. Blackwell(University of Michigan), Jette Bork‐Jensen(University of Copenhagen), Noël P. Burtt(Broad Institute), Yuhui Chen(Centre for Human Genetics), Todd J. Green(Broad Institute), Christopher Hartl(Broad Institute), Hyun Min Kang(University of Michigan), Ashish Kumar(Centre for Human Genetics), Claes Ladenvall(Lund University), Clement Ma(University of Michigan), Loukas Moutsianas(Centre for Human Genetics), Richard D. Pearson(Centre for Human Genetics), John R. B. Perry(Centre for Human Genetics), Nigel W. Rayner(Centre for Human Genetics), Neil R. Robertson(Centre for Human Genetics), Laura J. Scott(University of Michigan), Martijn van de Bunt(Centre for Human Genetics), Johan G. Eriksson(University of Helsinki), Antti Jula(Finnish Institute for Health and Welfare), Seppo Koskinen(Finnish Institute for Health and Welfare), Terho Lehtimäki(Tampere University), Aarno Palotie(Broad Institute), Olli T. Raitakari(University of Turku), Suzanne B.R. Jacobs(Broad Institute), Jennifer Wessel(Richard M. Fairbanks Foundation), Audrey Y. Chu(Brigham and Women's Hospital), Robert A. Scott(Wellcome/MRC Institute of Metabolic Science), Mark O. Goodarzi(Cedars-Sinai Medical Center), Christine Blancher(Centre for Human Genetics), Gemma Buck(Centre for Human Genetics), David Buck(Centre for Human Genetics), Peter S. Chines(National Institutes of Health), Stacey Gabriel(Broad Institute), Anette P. Gjesing(University of Copenhagen), Christopher J. Groves(Oxford Centre for Diabetes, Endocrinology and Metabolism), Mette Hollensted(University of Copenhagen), Jeroen R. Huyghe(University of Michigan), Anne Jackson(University of Michigan), Goo Jun(University of Michigan), Johanne Marie Justesen(University of Copenhagen), Massimo Mangino(King's College London), Jacquelyn Murphy(Broad Institute), Matt J. Neville(Oxford Centre for Diabetes, Endocrinology and Metabolism), Robert C. Onofrio(Broad Institute), Kerrin S. Small(King's College London), Heather M. Stringham(University of Michigan), Joseph Trakalo(Centre for Human Genetics), Eric Banks(Broad Institute), Jason Carey(Broad Institute), Mauricio O. Carneiro(Broad Institute), Mark A. DePristo(Broad Institute), Yossi Farjoun(Broad Institute), Timothy R. Fennell(Broad Institute), Jacqueline I. Goldstein(Broad Institute), George Grant(Broad Institute), Martin Hrabě de Angelis(Helmholtz Zentrum München), Jared Maguire(Broad Institute), Benjamin M. Neale(Broad Institute), Ryan Poplin(Broad Institute), Shaun Purcell(Broad Institute), Thomas Schwarzmayr(Helmholtz Zentrum München), Khalid Shakir(Broad Institute), Joshua D. Smith(University of Washington), Tim M. Strom(Helmholtz Zentrum München), Thomas Wieland(Helmholtz Zentrum München), Jaana Lindström(Finnish Institute for Health and Welfare), Ivan Brandslund(University of Southern Denmark), Cramer Christensen(Vejle Sygehus), Gabriela Surdulescu(King's College London), Timo A. Lakka(University of Eastern Finland), Alex S. F. Doney(Ninewells Hospital), Peter M. Nilsson(Lund University), Nicholas J. Wareham(Wellcome/MRC Institute of Metabolic Science), Claudia Langenberg(Wellcome/MRC Institute of Metabolic Science), Tibor V. Varga(Lund University), Paul W. Franks(Harvard University), Olov Rolandsson(Umeå University), Anders H. Rosengren(Lund University), Vidya S. Farook(Texas Biomedical Research Institute), Farook Thameem(The University of Texas at San Antonio Health Science Center), Sobha Puppala(Texas Biomedical Research Institute), Satish Kumar(Texas Biomedical Research Institute), Donna M. Lehman(The University of Texas at San Antonio Health Science Center), Christopher P. Jenkinson(The University of Texas at San Antonio Health Science Center), Joanne E. Curran(Texas Biomedical Research Institute), Daniel E. Hale(The University of Texas at San Antonio Health Science Center), Sharon P. Fowler(The University of Texas at San Antonio Health Science Center), Rector Arya(The University of Texas at San Antonio Health Science Center), Ralph A. DeFronzo(The University of Texas at San Antonio Health Science Center), Hanna E. Abboud(The University of Texas at San Antonio Health Science Center), Ann‐Christine Syvänen(Uppsala University), Pamela J. Hicks(Wake Forest University), Nicholette D. Palmer(Wake Forest University), Maggie C. Y. Ng(Wake Forest University), Donald W. Bowden(Wake Forest University), Barry I. Freedman(Wake Forest University), Tõnu Esko(Broad Institute), Reedik Mägi(University of Tartu), Lili Milani(University of Tartu), Evelin Mihailov(University of Tartu), Andres Metspalu(University of Tartu), Narisu Narisu(National Institutes of Health), Leena Kinnunen(Finnish Institute for Health and Welfare), Lori L. Bonnycastle(National Institutes of Health), Amy J. Swift(National Institutes of Health), Dorota Pasko(University of Exeter), Andrew R. Wood(University of Exeter), João Fadista(Lund University), Toni I. Pollin(University of Maryland, Baltimore), Nir Barzilai(Albert Einstein College of Medicine), Gil Atzmon(Albert Einstein College of Medicine), Benjamin Gläser(Hadassah Medical Center), Barbara Thorand(Helmholtz Zentrum München), Konstantin Strauch(Helmholtz Zentrum München), Annette Peters(Helmholtz Zentrum München), Michael Roden(Deutsches Diabetes-Zentrum e.V.), Martina Müller‐Nurasyid(Helmholtz Zentrum München), Liming Liang(Harvard University), Jennifer Kriebel(Helmholtz Zentrum München), Thomas Illig(Helmholtz Zentrum München), Harald Grallert(Helmholtz Zentrum München), Christian Gieger(Helmholtz Zentrum München), Christa Meisinger(Helmholtz Zentrum München), Lars Lannfelt(Uppsala University), Solomon K. Musani(Jackson Memorial Hospital), Michael Griswold(University of Mississippi Medical Center), Herman A. Taylor(University of Mississippi Medical Center), Gregory Wilson(Jackson State University), Adolfo Correa(University of Mississippi Medical Center), Heikki Oksa(Pirkanmaa Hospital District), William R. Scott(Imperial College London), Uzma Afzal(Imperial College London), Sian-Tsung Tan(Ealing Hospital), Marie Loh(Agency for Science, Technology and Research), John C. Chambers(Imperial College Healthcare NHS Trust), Jobanpreet Sehmi(Ealing Hospital), Jaspal S. Kooner(Lung Institute), Benjamin Lehne(Imperial College London), Yoon Shin Cho(Hallym University), Jong‐Young Lee(Ministry of Health and Welfare), Bok‐Ghee Han(Korea National Institute of Health), Annemari Käräjämäki(Vaasa Central Hospital), Qibin Qi(Albert Einstein College of Medicine), Lu Qi(Brigham and Women's Hospital), Jinyan Huang(Harvard University), Frank B. Hu(Harvard University), Olle Melander(Lund University), Marju Orho‐Melander(Lund University), Jennifer E. Below(The University of Texas Health Science Center at Houston), David Aguilar(Baylor College of Medicine), Tien Yin Wong(National University of Singapore), Jianjun Liu(Agency for Science, Technology and Research), Chiea Chuen Khor(Agency for Science, Technology and Research), Kee Seng Chia(National University of Singapore), Wei Yen Lim(National University of Singapore), Ching‐Yu Cheng(National University of Singapore), Edmund Chan(National University of Singapore), E Shyong Tai(National University of Singapore), Tin Aung(National University of Singapore), Allan Linneberg(University of Copenhagen), Bo Isomaa(Folkhälsans Forskningscentrum), Thomas Meitinger(Helmholtz Zentrum München), Tiinamaija Tuomi(Helsinki University Hospital), Liisa Hakaste(Folkhälsans Forskningscentrum), Jasmina Kravić(Lund University), Marit E. Jørgensen(Steno Diabetes Centers), Torsten Lauritzen(Aarhus University), Panos Deloukas(Wellcome Sanger Institute), Kathleen Stirrups(Queen Mary University of London), Katharine R. Owen(Oxford Centre for Diabetes, Endocrinology and Metabolism), Andrew J. Farmer(University of Oxford), Timothy M. Frayling(University of Exeter), Stephen O’Rahilly(Wellcome/MRC Institute of Metabolic Science), Mark Walker(Newcastle University), J Lévy(Oxford Centre for Diabetes, Endocrinology and Metabolism), Dylan Hodgkiss(King's College London), Andrew T. Hattersley(University of Exeter), Teemu Kuulasmaa(University of Eastern Finland), Alena Stančáková(University of Eastern Finland), Inês Barroso(Wellcome Sanger Institute), Dwaipayan Bharadwaj(Institute of Genomics and Integrative Biology), Juliana C.N. Chan(Chinese University of Hong Kong), Giriraj R. Chandak(Centre for Cellular and Molecular Biology), Mark J. Daly(Massachusetts General Hospital), Peter Donnelly(Centre for Human Genetics), Shah B. Ebrahim(Centre for Chronic Disease Control), Paul Elliott(Imperial College London), Tasha E. Fingerlin(Colorado School of Public Health), Philippe Froguel(Centre National de la Recherche Scientifique), Cheng Hu(Shanghai Jiao Tong University), Weiping Jia(Shanghai Jiao Tong University), Ronald C.W.(Chinese University of Hong Kong), Gilean McVean(Centre for Human Genetics), Taesung Park(Seoul National University), Dorairaj Prabhakaran(Centre for Chronic Disease Control), Manjinder S. Sandhu(University of Cambridge), James Scott(Lung Institute), Robert Sladek(McGill University and Génome Québec Innovation Centre), Nikhil Tandon(All India Institute of Medical Sciences), Yik Ying Teo(National University of Singapore), Eleftheria Zeggini(Wellcome Sanger Institute), Richard M. Watanabe(University of Southern California), Heikki A. Koistinen(University of Helsinki), Y. Antero Kesäniemi(University of Oulu), Matti Uusitupa(University of Eastern Finland), Timothy D. Spector(King's College London), Veikko Salomaa(Finnish Institute for Health and Welfare), Rainer Rauramaa, Colin N.A. Palmer(PharmacoGenetics (China)), Inga Prokopenko(Centre for Human Genetics), Andrew D. Morris(Centre for Human Genetics), Richard N. Bergman(Cedars-Sinai Medical Center), Francis S. Collins(National Institutes of Health), Lars Lind(Uppsala University), Erik Ingelsson(Uppsala University), Jaakko Tuomilehto(Universität für Weiterbildung Krems), Fredrik Karpe(Oxford Centre for Diabetes, Endocrinology and Metabolism), Leif Groop(Lund University), Torben Jørgensen(Glostrup Hospital), Torben Hansen(University of Copenhagen), Oluf Pedersen(University of Copenhagen), Johanna Kuusisto(University of Eastern Finland), Gonçalo R. Abecasis(University of Michigan), Graeme I. Bell(University of Chicago), John Blangero(Texas Biomedical Research Institute), Nancy J. Cox(University of Chicago), Ravindranath Duggirala(Texas Biomedical Research Institute), Mark Seielstad(University of California, San Francisco), James G. Wilson(University of Mississippi Medical Center), Josée Dupuis(Boston University), Samuli Ripatti(University of Helsinki), Craig L. Hanis(The University of Texas Health Science Center at Houston), José C. Florez(Broad Institute), Karen L. Mohlke(University of North Carolina at Chapel Hill), James B. Meigs(Broad Institute), Markku Laakso(University of Eastern Finland), Andrew P. Morris(Centre for Human Genetics), Michael Boehnke(University of Michigan), David Altshuler(Broad Institute), Mark I. McCarthy(Centre for Human Genetics), Anna L. Gloyn(Centre for Human Genetics), Cecilia M. Lindgren(Broad Institute)
Cited by 52Open Access
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.
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