Standard
A Low-Frequency Inactivating Akt2 Variant Enriched in the Finnish Population is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk. / 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 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 Marianne Prior; 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.
In:
Diabetes, Vol. 66, 12.2017, p. 2019-2032.
Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
Manning, A, Highland, HM, Gasser, J, Sim, X, Tukiainen, T, Fontanillas, P
, Grarup, N, Rivas, MA, Mahajan, A, Locke, AE, Cingolani, P
, Pers, TH, Viñuela, A, Brown, AA, Wu, Y, Flannick, J, Fuchsberger, C, Gamazon, ER, Gaulton, KJ, Im, HK, Teslovich, TM, Blackwell, TW, Bork-Jensen, J, Burtt, NP, Chen, Y, Green, T, Hartl, C, Kang, HM, Kumar, A, Ladenvall, C, Ma, C, Moutsianas, L, Pearson, RD, Perry, JRB, Rayner, NW, Robertson, NR, Scott, LJ, van de Bunt, M, Eriksson, JG, Jula, A, Koskinen, S, Lehtimäki, T, Palotie, A, Raitakari, OT, Jacobs, SB, Wessel, J, Chu, AY, Scott, RA, Goodarzi, MO, Blancher, C, Buck, G, Buck, D, Chines, PS, Gabriel, S, Gjesing, AMP, Groves, CJ, Hollensted, M, Huyghe, JR, Jackson, AU, Jun, G
, Justesen, JM, Mangino, M, Murphy, J, Neville, M, Onofrio, R, Small, KS, Stringham, HM, Trakalo, J, Banks, E, Carey, J, Carneiro, MO, DePristo, M, Farjoun, Y, Fennell, T, Goldstein, JI, Grant, G, Hrabé de Angelis, M, Maguire, J, Neale, BM, Poplin, R, Purcell, S, Schwarzmayr, T, Shakir, K, Smith, JD, Strom, TM, Wieland, T, Lindstrom, J, Brandslund, I, Christensen, C, Surdulescu, GL, Lakka, TA, Doney, ASF, Nilsson, P, Wareham, NJ, Langenberg, C
, Varga, TV, Franks, PW, Rolandsson, O, Rosengren, AH, Farook, VS, Thameem, F, Puppala, S, Kumar, S, Lehman, DM, Jenkinson, CP, Curran, JE, Hale, DE, Fowler, SP, Arya, R, DeFronzo, RA, Abboud, HE, Syvänen, A-C, Hicks, PJ, Palmer, ND, Ng, MCY, Bowden, DW, Freedman, BI, Esko, T, Mägi, R, Milani, L, Mihailov, E, Metspalu, A, Narisu, N, Kinnunen, L, Bonnycastle, LL, Swift, A, Pasko, D, Wood, AR, Fadista, J, Pollin, TI, Barzilai, N, Atzmon, G, Glaser, B, Thorand, B, Strauch, K, Peters, A, Roden, M, Müller-Nurasyid, M, Liang, L, Kriebel, J, Illig, T, Grallert, H, Gieger, C, Meisinger, C, Lannfelt, L, Musani, SK, Griswold, M, Taylor, HA, Wilson, G, Correa, A, Oksa, H, Scott, WR, Afzal, U, Tan, S-T, Loh, M, Chambers, JC, Sehmi, J, Kooner, JS, Lehne, B, Cho, YS, Lee, J-Y, Han, B-G, Käräjämäki, A, Qi, Q, Qi, L, Huang, J, Hu, FB, Melander, O, Orho-Melander, M, Below, JE, Aguilar, D, Wong, TY, Liu, J, Khor, C-C, Chia, KS, Lim, WY, Cheng, C-Y, Chan, E, Tai, ES, Aung, T
, Linneberg, A, Isomaa, B, Meitinger, T, Tuomi, T, Hakaste, L, Kravic, J, Jørgensen, ME, Lauritzen, T, Deloukas, P, Stirrups, KE, Owen, KR, Farmer, AJ, Frayling, TM, O'Rahilly, SP, Walker, M, Levy, JC, Hodgkiss, D, Hattersley, AT, Kuulasmaa, T, Stančáková, A, Barroso, I, Bharadwaj, D, Chan, J, Chandak, GR, Daly, MJ, Donnelly, PJ, Ebrahim, SB, Elliott, P, Fingerlin, T, Froguel, P, Hu, C, Jia, W, Ma, RCW, McVean, G, Park, T, Prabhakaran, D, Sandhu, M, Scott, J, Sladek, R, Tandon, N, Teo, YY, Zeggini, E, Watanabe, RM, Koistinen, HA, Kesaniemi, YA, Uusitupa, M, Spector, TD, Salomaa, V, Rauramaa, R, Palmer, CNA, Prokopenko, I, Morris, AD, Bergman, RN, Collins, FS, Lind, L, Ingelsson, E, Tuomilehto, J, Karpe, F, Groop, L, Jørgensen, T
, Hansen, T, Pedersen, O, Kuusisto, J, Abecasis, G, Bell, GI, Blangero, J, Cox, NJ, Duggirala, R, Seielstad, M, Wilson, JG, Dupuis, J, Ripatti, S, Hanis, CL, Florez, JC, Mohlke, KL, Meigs, JB, Laakso, M, Morris, AP, Boehnke, M, Altshuler, D, McCarthy, MI, Gloyn, AL & Lindgren, CM 2017, '
A Low-Frequency Inactivating Akt2 Variant Enriched in the Finnish Population is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk',
Diabetes, vol. 66, pp. 2019-2032.
https://doi.org/10.2337/db16-1329APA
Manning, A., Highland, H. M., Gasser, J., Sim, X., Tukiainen, T., Fontanillas, P.
, Grarup, N., Rivas, M. A., Mahajan, A., Locke, A. E., Cingolani, P.
, Pers, T. H., Viñuela, A., Brown, A. A., Wu, Y., Flannick, J., Fuchsberger, C., Gamazon, E. R., Gaulton, K. J., ... Lindgren, C. M. (2017).
A Low-Frequency Inactivating Akt2 Variant Enriched in the Finnish Population is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk.
Diabetes,
66, 2019-2032.
https://doi.org/10.2337/db16-1329Vancouver
Manning A, Highland HM, Gasser J, Sim X, Tukiainen T, Fontanillas P et al.
A Low-Frequency Inactivating Akt2 Variant Enriched in the Finnish Population is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk.
Diabetes. 2017 Dec;66:2019-2032.
https://doi.org/10.2337/db16-1329Author
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 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 Marianne Prior ; 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. / A Low-Frequency Inactivating Akt2 Variant Enriched in the Finnish Population is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk. In: Diabetes. 2017 ; Vol. 66. pp. 2019-2032.
Bibtex
@article{091b110fa4e345a6a88c109e32a9949c,
title = "A Low-Frequency Inactivating Akt2 Variant Enriched in the Finnish Population is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk",
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 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.",
keywords = "Journal Article",
author = "Alisa Manning and Highland, {Heather M} and Jessica Gasser and Xueling Sim and Taru Tukiainen and Pierre Fontanillas and Niels Grarup and Rivas, {Manuel A} and Anubha Mahajan and Locke, {Adam E} and Pablo Cingolani and Pers, {Tune H} and Ana Vi{\~n}uela and Brown, {Andrew A} and Ying Wu and Jason Flannick and Christian Fuchsberger and Gamazon, {Eric R} and Gaulton, {Kyle J} and Im, {Hae Kyung} and Teslovich, {Tanya M} and Blackwell, {Thomas W} and Jette Bork-Jensen and Burtt, {No{\"e}l P} and Yuhui Chen and Todd Green and Christopher Hartl and Kang, {Hyun Min} and Ashish Kumar and Claes Ladenvall and Clement Ma and Loukas Moutsianas and Pearson, {Richard D} and Perry, {John R B} and Rayner, {N William} and Robertson, {Neil R} and Scott, {Laura J} and {van de Bunt}, Martijn and Eriksson, {Johan G} and Antti Jula and Seppo Koskinen and Terho Lehtim{\"a}ki and Aarno Palotie and Raitakari, {Olli T} and Jacobs, {Suzanne Br} and Jennifer Wessel and Chu, {Audrey Y} and Scott, {Robert A} and Goodarzi, {Mark O} and Christine Blancher and Gemma Buck and David Buck and Chines, {Peter S} and Stacey Gabriel and Gjesing, {Anette Marianne Prior} and Groves, {Christopher J} and Mette Hollensted and Huyghe, {Jeroen R} and Jackson, {Anne U} and Goo Jun and Justesen, {Johanne Marie} and Massimo Mangino and Jacquelyn Murphy and Matt Neville and Robert Onofrio and Small, {Kerrin S} and Stringham, {Heather M} and Joseph Trakalo and Eric Banks and Jason Carey and Carneiro, {Mauricio O} and Mark DePristo and Yossi Farjoun and Timothy Fennell and Goldstein, {Jacqueline I} and George Grant and {Hrab{\'e} de Angelis}, Martin and Jared Maguire and Neale, {Benjamin M} and Ryan Poplin and Shaun Purcell and Thomas Schwarzmayr and Khalid Shakir and Smith, {Joshua D} and Strom, {Tim M} and Thomas Wieland and Jaana Lindstrom and Ivan Brandslund and Cramer Christensen and Surdulescu, {Gabriela L} and Lakka, {Timo A} and Doney, {Alex S F} and Peter Nilsson and Wareham, {Nicholas J} and Claudia Langenberg and Varga, {Tibor V} and Franks, {Paul W} and Olov Rolandsson and Rosengren, {Anders H} and Farook, {Vidya S} and Farook Thameem and Sobha Puppala and Satish Kumar and Lehman, {Donna M} and Jenkinson, {Christopher P} and Curran, {Joanne E} and Hale, {Daniel Esten} and Fowler, {Sharon P} and Rector Arya and DeFronzo, {Ralph A} and Abboud, {Hanna E} and Ann-Christine Syv{\"a}nen and Hicks, {Pamela J} and Palmer, {Nicholette D} and Ng, {Maggie C Y} and Bowden, {Donald W} and Freedman, {Barry I} and T{\~o}nu Esko and Reedik M{\"a}gi and Lili Milani and Evelin Mihailov and Andres Metspalu and Narisu Narisu and Leena Kinnunen and Bonnycastle, {Lori L} and Amy Swift and Dorota Pasko and Wood, {Andrew R} and Jo{\~a}o Fadista and Pollin, {Toni I} and Nir Barzilai and Gil Atzmon and Benjamin Glaser and Barbara Thorand and Konstantin Strauch and Annette Peters and Michael Roden and Martina M{\"u}ller-Nurasyid and Liming Liang and Jennifer Kriebel and Thomas Illig and Harald Grallert and Christian Gieger and Christa Meisinger and Lars Lannfelt and Musani, {Solomon K} and Michael Griswold and Taylor, {Herman A} and Gregory Wilson and Adolfo Correa and Heikki Oksa and Scott, {William R} and Uzma Afzal and Sian-Tsung Tan and Marie Loh and Chambers, {John C} and Jobanpreet Sehmi and Kooner, {Jaspal Singh} and Benjamin Lehne and Cho, {Yoon Shin} and Jong-Young Lee and Bok-Ghee Han and Annemari K{\"a}r{\"a}j{\"a}m{\"a}ki and Qibin Qi and Lu Qi and Jinyan Huang and Hu, {Frank B} and Olle Melander and Marju Orho-Melander and Below, {Jennifer E} and David Aguilar and Wong, {Tien Yin} and Jianjun Liu and Chiea-Chuen Khor and Chia, {Kee Seng} and Lim, {Wei Yen} and Ching-Yu Cheng and Edmund Chan and Tai, {E Shyong} and Tin Aung and Allan Linneberg and Bo Isomaa and Thomas Meitinger and Tiinamaija Tuomi and Liisa Hakaste and Jasmina Kravic and J{\o}rgensen, {Marit E} and Torsten Lauritzen and Panos Deloukas and Stirrups, {Kathleen E} and Owen, {Katharine R} and Farmer, {Andrew J} and Frayling, {Timothy M} and O'Rahilly, {Stephen P} and Mark Walker and Levy, {Jonathan C} and Dylan Hodgkiss and Hattersley, {Andrew T} and Teemu Kuulasmaa and Alena Stan{\v c}{\'a}kov{\'a} and In{\^e}s Barroso and Dwaipayan Bharadwaj and Juliana Chan and Chandak, {Giriraj R} and Daly, {Mark J} and Donnelly, {Peter J} and Ebrahim, {Shah B} and Paul Elliott and Tasha Fingerlin and Philippe Froguel and Cheng Hu and Weiping Jia and Ma, {Ronald C W} and Gilean McVean and Taesung Park and Dorairaj Prabhakaran and Manjinder Sandhu and James Scott and Rob Sladek and Nikhil Tandon and Teo, {Yik Ying} and Eleftheria Zeggini and Watanabe, {Richard M} and Koistinen, {Heikki A} and Kesaniemi, {Y Antero} and Matti Uusitupa and Spector, {Timothy D} and Veikko Salomaa and Rainer Rauramaa and Palmer, {Colin N A} and Inga Prokopenko and Morris, {Andrew D} and Bergman, {Richard N} and Collins, {Francis S} and Lars Lind and Erik Ingelsson and Jaakko Tuomilehto and Fredrik Karpe and Leif Groop and Torben J{\o}rgensen and Torben Hansen and Oluf Pedersen and Johanna Kuusisto and Gon{\c c}alo Abecasis and Bell, {Graeme I} and John Blangero and Cox, {Nancy J} and Ravindranath Duggirala and Mark Seielstad and Wilson, {James G} and Josee Dupuis and Samuli Ripatti and Hanis, {Craig L} and Florez, {Jose C} and Mohlke, {Karen L} and Meigs, {James B} and Markku Laakso and Morris, {Andrew P} and Michael Boehnke and David Altshuler and McCarthy, {Mark I} and Gloyn, {Anna L} and Lindgren, {Cecilia M}",
note = "{\textcopyright} 2017 by the American Diabetes Association.",
year = "2017",
month = dec,
doi = "10.2337/db16-1329",
language = "English",
volume = "66",
pages = "2019--2032",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association",
}
RIS
TY - JOUR
T1 - A Low-Frequency Inactivating Akt2 Variant Enriched in the Finnish Population is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk
AU - Manning, Alisa
AU - Highland, Heather M
AU - Gasser, Jessica
AU - Sim, Xueling
AU - Tukiainen, Taru
AU - Fontanillas, Pierre
AU - Grarup, Niels
AU - Rivas, Manuel A
AU - Mahajan, Anubha
AU - Locke, Adam E
AU - Cingolani, Pablo
AU - Pers, Tune H
AU - Viñuela, Ana
AU - Brown, Andrew A
AU - Wu, Ying
AU - Flannick, Jason
AU - Fuchsberger, Christian
AU - Gamazon, Eric R
AU - Gaulton, Kyle J
AU - Im, Hae Kyung
AU - Teslovich, Tanya M
AU - Blackwell, Thomas W
AU - Bork-Jensen, Jette
AU - Burtt, Noël P
AU - Chen, Yuhui
AU - Green, Todd
AU - Hartl, Christopher
AU - Kang, Hyun Min
AU - Kumar, Ashish
AU - Ladenvall, Claes
AU - Ma, Clement
AU - Moutsianas, Loukas
AU - Pearson, Richard D
AU - Perry, John R B
AU - Rayner, N William
AU - Robertson, Neil R
AU - Scott, Laura J
AU - van de Bunt, Martijn
AU - Eriksson, Johan G
AU - Jula, Antti
AU - Koskinen, Seppo
AU - Lehtimäki, Terho
AU - Palotie, Aarno
AU - Raitakari, Olli T
AU - Jacobs, Suzanne Br
AU - Wessel, Jennifer
AU - Chu, Audrey Y
AU - Scott, Robert A
AU - Goodarzi, Mark O
AU - Blancher, Christine
AU - Buck, Gemma
AU - Buck, David
AU - Chines, Peter S
AU - Gabriel, Stacey
AU - Gjesing, Anette Marianne Prior
AU - Groves, Christopher J
AU - Hollensted, Mette
AU - Huyghe, Jeroen R
AU - Jackson, Anne U
AU - Jun, Goo
AU - Justesen, Johanne Marie
AU - Mangino, Massimo
AU - Murphy, Jacquelyn
AU - Neville, Matt
AU - Onofrio, Robert
AU - Small, Kerrin S
AU - Stringham, Heather M
AU - Trakalo, Joseph
AU - Banks, Eric
AU - Carey, Jason
AU - Carneiro, Mauricio O
AU - DePristo, Mark
AU - Farjoun, Yossi
AU - Fennell, Timothy
AU - Goldstein, Jacqueline I
AU - Grant, George
AU - Hrabé de Angelis, Martin
AU - Maguire, Jared
AU - Neale, Benjamin M
AU - Poplin, Ryan
AU - Purcell, Shaun
AU - Schwarzmayr, Thomas
AU - Shakir, Khalid
AU - Smith, Joshua D
AU - Strom, Tim M
AU - Wieland, Thomas
AU - Lindstrom, Jaana
AU - Brandslund, Ivan
AU - Christensen, Cramer
AU - Surdulescu, Gabriela L
AU - Lakka, Timo A
AU - Doney, Alex S F
AU - Nilsson, Peter
AU - Wareham, Nicholas J
AU - Langenberg, Claudia
AU - Varga, Tibor V
AU - Franks, Paul W
AU - Rolandsson, Olov
AU - Rosengren, Anders H
AU - Farook, Vidya S
AU - Thameem, Farook
AU - Puppala, Sobha
AU - Kumar, Satish
AU - Lehman, Donna M
AU - Jenkinson, Christopher P
AU - Curran, Joanne E
AU - Hale, Daniel Esten
AU - Fowler, Sharon P
AU - Arya, Rector
AU - DeFronzo, Ralph A
AU - Abboud, Hanna E
AU - Syvänen, Ann-Christine
AU - Hicks, Pamela J
AU - Palmer, Nicholette D
AU - Ng, Maggie C Y
AU - Bowden, Donald W
AU - Freedman, Barry I
AU - Esko, Tõnu
AU - Mägi, Reedik
AU - Milani, Lili
AU - Mihailov, Evelin
AU - Metspalu, Andres
AU - Narisu, Narisu
AU - Kinnunen, Leena
AU - Bonnycastle, Lori L
AU - Swift, Amy
AU - Pasko, Dorota
AU - Wood, Andrew R
AU - Fadista, João
AU - Pollin, Toni I
AU - Barzilai, Nir
AU - Atzmon, Gil
AU - Glaser, Benjamin
AU - Thorand, Barbara
AU - Strauch, Konstantin
AU - Peters, Annette
AU - Roden, Michael
AU - Müller-Nurasyid, Martina
AU - Liang, Liming
AU - Kriebel, Jennifer
AU - Illig, Thomas
AU - Grallert, Harald
AU - Gieger, Christian
AU - Meisinger, Christa
AU - Lannfelt, Lars
AU - Musani, Solomon K
AU - Griswold, Michael
AU - Taylor, Herman A
AU - Wilson, Gregory
AU - Correa, Adolfo
AU - Oksa, Heikki
AU - Scott, William R
AU - Afzal, Uzma
AU - Tan, Sian-Tsung
AU - Loh, Marie
AU - Chambers, John C
AU - Sehmi, Jobanpreet
AU - Kooner, Jaspal Singh
AU - Lehne, Benjamin
AU - Cho, Yoon Shin
AU - Lee, Jong-Young
AU - Han, Bok-Ghee
AU - Käräjämäki, Annemari
AU - Qi, Qibin
AU - Qi, Lu
AU - Huang, Jinyan
AU - Hu, Frank B
AU - Melander, Olle
AU - Orho-Melander, Marju
AU - Below, Jennifer E
AU - Aguilar, David
AU - Wong, Tien Yin
AU - Liu, Jianjun
AU - Khor, Chiea-Chuen
AU - Chia, Kee Seng
AU - Lim, Wei Yen
AU - Cheng, Ching-Yu
AU - Chan, Edmund
AU - Tai, E Shyong
AU - Aung, Tin
AU - Linneberg, Allan
AU - Isomaa, Bo
AU - Meitinger, Thomas
AU - Tuomi, Tiinamaija
AU - Hakaste, Liisa
AU - Kravic, Jasmina
AU - Jørgensen, Marit E
AU - Lauritzen, Torsten
AU - Deloukas, Panos
AU - Stirrups, Kathleen E
AU - Owen, Katharine R
AU - Farmer, Andrew J
AU - Frayling, Timothy M
AU - O'Rahilly, Stephen P
AU - Walker, Mark
AU - Levy, Jonathan C
AU - Hodgkiss, Dylan
AU - Hattersley, Andrew T
AU - Kuulasmaa, Teemu
AU - Stančáková, Alena
AU - Barroso, Inês
AU - Bharadwaj, Dwaipayan
AU - Chan, Juliana
AU - Chandak, Giriraj R
AU - Daly, Mark J
AU - Donnelly, Peter J
AU - Ebrahim, Shah B
AU - Elliott, Paul
AU - Fingerlin, Tasha
AU - Froguel, Philippe
AU - Hu, Cheng
AU - Jia, Weiping
AU - Ma, Ronald C W
AU - McVean, Gilean
AU - Park, Taesung
AU - Prabhakaran, Dorairaj
AU - Sandhu, Manjinder
AU - Scott, James
AU - Sladek, Rob
AU - Tandon, Nikhil
AU - Teo, Yik Ying
AU - Zeggini, Eleftheria
AU - Watanabe, Richard M
AU - Koistinen, Heikki A
AU - Kesaniemi, Y Antero
AU - Uusitupa, Matti
AU - Spector, Timothy D
AU - Salomaa, Veikko
AU - Rauramaa, Rainer
AU - Palmer, Colin N A
AU - Prokopenko, Inga
AU - Morris, Andrew D
AU - Bergman, Richard N
AU - Collins, Francis S
AU - Lind, Lars
AU - Ingelsson, Erik
AU - Tuomilehto, Jaakko
AU - Karpe, Fredrik
AU - Groop, Leif
AU - Jørgensen, Torben
AU - Hansen, Torben
AU - Pedersen, Oluf
AU - Kuusisto, Johanna
AU - Abecasis, Gonçalo
AU - Bell, Graeme I
AU - Blangero, John
AU - Cox, Nancy J
AU - Duggirala, Ravindranath
AU - Seielstad, Mark
AU - Wilson, James G
AU - Dupuis, Josee
AU - Ripatti, Samuli
AU - Hanis, Craig L
AU - Florez, Jose C
AU - Mohlke, Karen L
AU - Meigs, James B
AU - Laakso, Markku
AU - Morris, Andrew P
AU - Boehnke, Michael
AU - Altshuler, David
AU - McCarthy, Mark I
AU - Gloyn, Anna L
AU - Lindgren, Cecilia M
N1 - © 2017 by the American Diabetes Association.
PY - 2017/12
Y1 - 2017/12
N2 - 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.
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 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.
KW - Journal Article
U2 - 10.2337/db16-1329
DO - 10.2337/db16-1329
M3 - Journal article
C2 - 28341696
VL - 66
SP - 2019
EP - 2032
JO - Diabetes
JF - Diabetes
SN - 0012-1797
ER -
