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

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Manning, Alisa, Highland, Heather M, Gasser, Jessica, Sim, Xueling, Tukiainen, Taru, Fontanillas, Pierre, Grarup, Niels, Rivas, Manuel A, Mahajan, Anubha, Locke, Adam E et al (show 253 more authors) , Cingolani, Pablo, Pers, Tune H, Vinuela, 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, Noel P, Chen, Yuhui, Green, Todd, Hartl, Christopher, Kang, Hyun Min, Kumar, Ashish, Ladenvall, Claes, Ma, Clement, Moutsianas, Loukas, Pearson, Richard D, Perry, John RB, Rayner, N William, Robertson, Neil R, Scott, Laura J, van de Bunt, Martijn, Eriksson, Johan G, Jula, Antti, Koskinen, Seppo, Lehtimaki, Terho, Palotie, Aarno, Raitakari, Olli T, Jacobs, Suzanne BR, 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, de Angelis, Martin Hrabe, 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 SF, 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, Syvanen, Ann-Christine, Hicks, Pamela J, Palmer, Nicholette D, Ng, Maggie CY, Bowden, Donald W, Freedman, Barry I, Esko, Tonu, Magi, Reedik, Milani, Lili, Mihailov, Evelin, Metspalu, Andres, Narisu, Narisu, Kinnunen, Leena, Bonnycastle, Lori L, Swift, Amy, Pasko, Dorota, Wood, Andrew R, Fadista, Joao, Pollin, Toni I, Barzilai, Nir, Atzmon, Gil, Glaser, Benjamin, Thorand, Barbara, Strauch, Konstantin, Peters, Annette, Roden, Michael, Mueller-Nurasyid, Martina, Liang, Liming, Kriebel, Jennifer, Illig, Thomas, Grallert, Harald, Gieger, Christian, Meisinger, Christa, Lannfelt, Lars, Musani, Solomon K, Griswold, Michael, Taylor, Herman A Jr, Wilson, Gregory Sr, 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, Karajamaki, 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, Jorgensen, 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, Stancakova, Alena, Barroso, Ines, 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 CW, 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 NA, Prokopenko, Inga, Morris, Andrew D, Bergman, Richard N, Collins, Francis S, Lind, Lars, Ingelsson, Erik, Tuomilehto, Jaakko, Karpe, Fredrik, Groop, Leif, Jorgensen, Torben, Hansen, Torben, Pedersen, Oluf, Kuusisto, Johanna, Abecasis, GonOalo, 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 and Lindgren, Cecilia M (2017) A Low-Frequency Inactivating <i>AKT2</i> Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk. DIABETES, 66 (7). pp. 2019-2032.

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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 <i>AKT2</i> 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 <i>AKT2</i> associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of <i>AKT2</i>.

Item Type:	Article
Uncontrolled Keywords:	Humans, Diabetes Mellitus, Type 2, Insulin Resistance, Genetic Predisposition to Disease, Insulin, Fasting, Odds Ratio, Case-Control Studies, Gene Frequency, Genotype, Alleles, Finland, Proto-Oncogene Proteins c-akt, Hispanic or Latino, Asian People, White People, Black or African American
Depositing User:	Symplectic Admin
Date Deposited:	10 Apr 2017 06:34
Last Modified:	05 Oct 2023 14:50
DOI:	10.2337/db16-1329
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3006899