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

description: 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 insulin, 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 fasting plasma insulin (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-hour 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.