RT Journal Article SR Electronic T1 A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk JF Diabetes JO Diabetes FD American Diabetes Association SP 2019 OP 2032 DO 10.2337/db16-1329 VO 66 IS 7 A1 Manning, Alisa A1 Highland, Heather M. A1 Gasser, Jessica A1 Sim, Xueling A1 Tukiainen, Taru A1 Fontanillas, Pierre A1 Grarup, Niels A1 Rivas, Manuel A. A1 Mahajan, Anubha A1 Locke, Adam E. A1 Cingolani, Pablo A1 Pers, Tune H. A1 Viñuela, Ana A1 Brown, Andrew A. A1 Wu, Ying A1 Flannick, Jason A1 Fuchsberger, Christian A1 Gamazon, Eric R. A1 Gaulton, Kyle J. A1 Im, Hae Kyung A1 Teslovich, Tanya M. A1 Blackwell, Thomas W. A1 Bork-Jensen, Jette A1 Burtt, Noël P. A1 Chen, Yuhui A1 Green, Todd A1 Hartl, Christopher A1 Kang, Hyun Min A1 Kumar, Ashish A1 Ladenvall, Claes A1 Ma, Clement A1 Moutsianas, Loukas A1 Pearson, Richard D. A1 Perry, John R.B. A1 Rayner, N. William A1 Robertson, Neil R. A1 Scott, Laura J. A1 van de Bunt, Martijn A1 Eriksson, Johan G. A1 Jula, Antti A1 Koskinen, Seppo A1 Lehtimäki, Terho A1 Palotie, Aarno A1 Raitakari, Olli T. A1 Jacobs, Suzanne B.R. A1 Wessel, Jennifer A1 Chu, Audrey Y. A1 Scott, Robert A. A1 Goodarzi, Mark O. A1 Blancher, Christine A1 Buck, Gemma A1 Buck, David A1 Chines, Peter S. A1 Gabriel, Stacey A1 Gjesing, Anette P. A1 Groves, Christopher J. A1 Hollensted, Mette A1 Huyghe, Jeroen R. A1 Jackson, Anne U. A1 Jun, Goo A1 Justesen, Johanne Marie A1 Mangino, Massimo A1 Murphy, Jacquelyn A1 Neville, Matt A1 Onofrio, Robert A1 Small, Kerrin S. A1 Stringham, Heather M. A1 Trakalo, Joseph A1 Banks, Eric A1 Carey, Jason A1 Carneiro, Mauricio O. A1 DePristo, Mark A1 Farjoun, Yossi A1 Fennell, Timothy A1 Goldstein, Jacqueline I. A1 Grant, George A1 Hrabé de Angelis, Martin A1 Maguire, Jared A1 Neale, Benjamin M. A1 Poplin, Ryan A1 Purcell, Shaun A1 Schwarzmayr, Thomas A1 Shakir, Khalid A1 Smith, Joshua D. A1 Strom, Tim M. A1 Wieland, Thomas A1 Lindstrom, Jaana A1 Brandslund, Ivan A1 Christensen, Cramer A1 Surdulescu, Gabriela L. A1 Lakka, Timo A. A1 Doney, Alex S.F. A1 Nilsson, Peter A1 Wareham, Nicholas J. A1 Langenberg, Claudia A1 Varga, Tibor V. A1 Franks, Paul W. A1 Rolandsson, Olov A1 Rosengren, Anders H. A1 Farook, Vidya S. A1 Thameem, Farook A1 Puppala, Sobha A1 Kumar, Satish A1 Lehman, Donna M. A1 Jenkinson, Christopher P. A1 Curran, Joanne E. A1 Hale, Daniel Esten A1 Fowler, Sharon P. A1 Arya, Rector A1 DeFronzo, Ralph A. A1 Abboud, Hanna E. A1 Syvänen, Ann-Christine A1 Hicks, Pamela J. A1 Palmer, Nicholette D. A1 Ng, Maggie C.Y. A1 Bowden, Donald W. A1 Freedman, Barry I. A1 Esko, Tõnu A1 Mägi, Reedik A1 Milani, Lili A1 Mihailov, Evelin A1 Metspalu, Andres A1 Narisu, Narisu A1 Kinnunen, Leena A1 Bonnycastle, Lori L. A1 Swift, Amy A1 Pasko, Dorota A1 Wood, Andrew R. A1 Fadista, João A1 Pollin, Toni I. A1 Barzilai, Nir A1 Atzmon, Gil A1 Glaser, Benjamin A1 Thorand, Barbara A1 Strauch, Konstantin A1 Peters, Annette A1 Roden, Michael A1 Müller-Nurasyid, Martina A1 Liang, Liming A1 Kriebel, Jennifer A1 Illig, Thomas A1 Grallert, Harald A1 Gieger, Christian A1 Meisinger, Christa A1 Lannfelt, Lars A1 Musani, Solomon K. A1 Griswold, Michael A1 Taylor, Herman A. A1 Wilson, Gregory A1 Correa, Adolfo A1 Oksa, Heikki A1 Scott, William R. A1 Afzal, Uzma A1 Tan, Sian-Tsung A1 Loh, Marie A1 Chambers, John C. A1 Sehmi, Jobanpreet A1 Kooner, Jaspal Singh A1 Lehne, Benjamin A1 Cho, Yoon Shin A1 Lee, Jong-Young A1 Han, Bok-Ghee A1 Käräjämäki, Annemari A1 Qi, Qibin A1 Qi, Lu A1 Huang, Jinyan A1 Hu, Frank B. A1 Melander, Olle A1 Orho-Melander, Marju A1 Below, Jennifer E. A1 Aguilar, David A1 Wong, Tien Yin A1 Liu, Jianjun A1 Khor, Chiea-Chuen A1 Chia, Kee Seng A1 Lim, Wei Yen A1 Cheng, Ching-Yu A1 Chan, Edmund A1 Tai, E Shyong A1 Aung, Tin A1 Linneberg, Allan A1 Isomaa, Bo A1 Meitinger, Thomas A1 Tuomi, Tiinamaija A1 Hakaste, Liisa A1 Kravic, Jasmina A1 Jørgensen, Marit E. A1 Lauritzen, Torsten A1 Deloukas, Panos A1 Stirrups, Kathleen E. A1 Owen, Katharine R. A1 Farmer, Andrew J. A1 Frayling, Timothy M. A1 O'Rahilly, Stephen P. A1 Walker, Mark A1 Levy, Jonathan C. A1 Hodgkiss, Dylan A1 Hattersley, Andrew T. A1 Kuulasmaa, Teemu A1 Stančáková, Alena A1 Barroso, Inês A1 Bharadwaj, Dwaipayan A1 Chan, Juliana A1 Chandak, Giriraj R. A1 Daly, Mark J. A1 Donnelly, Peter J. A1 Ebrahim, Shah B. A1 Elliott, Paul A1 Fingerlin, Tasha A1 Froguel, Philippe A1 Hu, Cheng A1 Jia, Weiping A1 Ma, Ronald C.W. A1 McVean, Gilean A1 Park, Taesung A1 Prabhakaran, Dorairaj A1 Sandhu, Manjinder A1 Scott, James A1 Sladek, Rob A1 Tandon, Nikhil A1 Teo, Yik Ying A1 Zeggini, Eleftheria A1 Watanabe, Richard M. A1 Koistinen, Heikki A. A1 Kesaniemi, Y. Antero A1 Uusitupa, Matti A1 Spector, Timothy D. A1 Salomaa, Veikko A1 Rauramaa, Rainer A1 Palmer, Colin N.A. A1 Prokopenko, Inga A1 Morris, Andrew D. A1 Bergman, Richard N. A1 Collins, Francis S. A1 Lind, Lars A1 Ingelsson, Erik A1 Tuomilehto, Jaakko A1 Karpe, Fredrik A1 Groop, Leif A1 Jørgensen, Torben A1 Hansen, Torben A1 Pedersen, Oluf A1 Kuusisto, Johanna A1 Abecasis, Gonçalo A1 Bell, Graeme I. A1 Blangero, John A1 Cox, Nancy J. A1 Duggirala, Ravindranath A1 Seielstad, Mark A1 Wilson, James G. A1 Dupuis, Josee A1 Ripatti, Samuli A1 Hanis, Craig L. A1 Florez, Jose C. A1 Mohlke, Karen L. A1 Meigs, James B. A1 Laakso, Markku A1 Morris, Andrew P. A1 Boehnke, Michael A1 Altshuler, David A1 McCarthy, Mark I. A1 Gloyn, Anna L. A1 Lindgren, Cecilia M. YR 2017 UL http://diabetes.diabetesjournals.org/content/66/7/2019.abstract AB 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.