A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk
Authors: Manning Alisa , Highland Heather M. , Gasser Jessica , Sim Xueling , Tukiainen Taru , Fontanillas Pierre , Grarup Niels , Rivas Manuel A. , Mahajan Anubha , Locke Adam E. , Cingolani Pablo , Pers Tune H. , Viñuela Ana , Brown Andrew A. , Wu Ying , Flannick Jason , Fuchsberger Christian , Gamazon Eric R. , Gaulton Kyle J. , Im Hae Kyung , Teslovich Tanya M. , Blackwell Thomas W. , Bork-Jensen Jette , Burtt Noël P. , Chen Yuhui , Green Todd , Hartl Christopher , Kang Hyun Min , Kumar Ashish , Ladenvall Claes , Ma Clement , Moutsianas Loukas , Pearson Richard D. , Perry John R.B. , Rayner N. William , Robertson Neil R. , Scott Laura J. , van de Bunt Martijn , Eriksson Johan G. , Jula Antti , Koskinen Seppo , Lehtimäki Terho , Palotie Aarno , Raitakari Olli T. , Jacobs Suzanne B.R. , Wessel Jennifer , Chu Audrey Y. , Scott Robert A. , Goodarzi Mark O. , Blancher Christine , Buck Gemma , Buck David , Chines Peter S. , Gabriel Stacey , Gjesing Anette P. , Groves Christopher J. , Hollensted Mette , Huyghe Jeroen R. , Jackson Anne U. , Jun Goo , Justesen Johanne Marie , Mangino Massimo , Murphy Jacquelyn , Neville Matt , Onofrio Robert , Small Kerrin S. , Stringham Heather M. , Trakalo Joseph , Banks Eric , Carey Jason , Carneiro Mauricio O. , DePristo Mark , Farjoun Yossi , Fennell Timothy , Goldstein Jacqueline I. , Grant George , Hrabé de Angelis Martin , Maguire Jared , Neale Benjamin M. , Poplin Ryan , Purcell Shaun , Schwarzmayr Thomas , Shakir Khalid , Smith Joshua D. , Strom Tim M. , Wieland Thomas , Lindstrom Jaana , Brandslund Ivan , Christensen Cramer , Surdulescu Gabriela L. , Lakka Timo A. , Doney Alex S.F. , Nilsson Peter , Wareham Nicholas J. , Langenberg Claudia , Varga Tibor V. , Franks Paul W. , Rolandsson Olov , Rosengren Anders H. , Farook Vidya S. , Thameem Farook , Puppala Sobha , Kumar Satish , Lehman Donna M. , Jenkinson Christopher P. , Curran Joanne E. , Hale Daniel Esten , Fowler Sharon P. , Arya Rector , DeFronzo Ralph A. , Abboud Hanna E. , Syvänen Ann-Christine , Hicks Pamela J. , Palmer Nicholette D. , Ng Maggie C.Y. , Bowden Donald W. , Freedman Barry I. , Esko Tõnu , Mägi Reedik , Milani Lili , Mihailov Evelin , Metspalu Andres , Narisu Narisu , Kinnunen Leena , Bonnycastle Lori L. , Swift Amy , Pasko Dorota , Wood Andrew R. , Fadista João , Pollin Toni I. , Barzilai Nir , Atzmon Gil , Glaser Benjamin , Thorand Barbara , Strauch Konstantin , Peters Annette , Roden Michael , Müller-Nurasyid Martina , Liang Liming , Kriebel Jennifer , Illig Thomas , Grallert Harald , Gieger Christian , Meisinger Christa , Lannfelt Lars , Musani Solomon K. , Griswold Michael , Taylor Herman A. , Wilson Gregory , Correa Adolfo , Oksa Heikki , Scott William R. , Afzal Uzma , Tan Sian-Tsung , Loh Marie , Chambers John C. , Sehmi Jobanpreet , Kooner Jaspal Singh , Lehne Benjamin , Cho Yoon Shin , Lee Jong-Young , Han Bok-Ghee , Käräjämäki Annemari , Qi Qibin , Qi Lu , Huang Jinyan , Hu Frank B. , Melander Olle , Orho-Melander Marju , Below Jennifer E. , Aguilar David , Wong Tien Yin , Liu Jianjun , Khor Chiea-Chuen , Chia Kee Seng , Lim Wei Yen , Cheng Ching-Yu , Chan Edmund , Tai E Shyong , Aung Tin , Linneberg Allan , Isomaa Bo , Meitinger Thomas , Tuomi Tiinamaija , Hakaste Liisa , Kravic Jasmina , Jørgensen Marit E. , Lauritzen Torsten , Deloukas Panos , Stirrups Kathleen E. , Owen Katharine R. , Farmer Andrew J. , Frayling Timothy M. , O'Rahilly Stephen P. , Walker Mark , Levy Jonathan C. , Hodgkiss Dylan , Hattersley Andrew T. , Kuulasmaa Teemu , Stančáková Alena , Barroso Inês , Bharadwaj Dwaipayan , Chan Juliana , Chandak Giriraj R. , Daly Mark J. , Donnelly Peter J. , Ebrahim Shah B. , Elliott Paul , Fingerlin Tasha , Froguel Philippe , Hu Cheng , Jia Weiping , Ma Ronald C.W. , McVean Gilean , Park Taesung , Prabhakaran Dorairaj , Sandhu Manjinder , Scott James , Sladek Rob , Tandon Nikhil , Teo Yik Ying , Zeggini Eleftheria , Watanabe Richard M. , Koistinen Heikki A. , Kesaniemi Y. Antero , Uusitupa Matti , Spector Timothy D. , Salomaa Veikko , Rauramaa Rainer , Palmer Colin N.A. , Prokopenko Inga , Morris Andrew D. , Bergman Richard N. , Collins Francis S. , Lind Lars , Ingelsson Erik , Tuomilehto Jaakko , Karpe Fredrik , Groop Leif , Jørgensen Torben , Hansen Torben , Pedersen Oluf , Kuusisto Johanna , Abecasis Gonçalo , Bell Graeme I. , Blangero John , Cox Nancy J. , Duggirala Ravindranath , Seielstad Mark , Wilson James G. , Dupuis Josee , Ripatti Samuli , Hanis Craig L. , Florez Jose C. , Mohlke Karen L. , Meigs James B. , Laakso Markku , Morris Andrew P. , Boehnke Michael , Altshuler David , McCarthy Mark I. , Gloyn Anna L. , Lindgren Cecilia M. 
Published: March 2017

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.