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

Alisa K Manning, Heather M Highland, Jessica Gasser, Xueling Sim, Taru Tukiainen, Pierre Fontanillas, Niels Grarup, Manuel A Rivas, Anubha Mahajan, Adam E Locke, Pablo Cingolani, Tune H Pers, Ana Viñuela, Andrew Brown, Ying Wu, Jason Flannick, Christian Fuchsberger, Eric R Gamazon, Kyle J Gaulton, Hae Kyung Im & 243 andre Tanya M Teslovich, Thomas W Blackwell, Jette Bork-Jensen, Noël P Burtt, Yuhui Chen, Todd Green, Christopher Hartl, Hyun Min Kang, Ashish Kumar, Claes Ladenvall, Clement Ma, Loukas Moutsianas, Richard D Pearson, John R B Perry, N William Rayner, Neil R Robertson, Laura J Scott, Martijn van de Bunt, Johan G Eriksson, Antti Jula, Seppo Koskinen, Terho Lehtimäki, Aarno Palotie, Olli T Raitakari, Suzanne B R Jacobs, Jennifer Wessel, Audrey Y Chu, Robert A Scott, Mark O Goodarzi, Christine Blancher, Gemma Buck, David Buck, Peter S Chines, Stacey B Gabriel, Anette P. Gjesing, Christopher J Groves, Mette Hollensted, Jeroen R Huyghe, Anne U Jackson, Goo Jun, Johanne Marie Justesen, Massimo Mangino, Jacquelyn Murphy, Matt J Neville, Robert Onofrio, Kerrin S Small, Heather M Stringham, Joseph Trakalo, Eric Banks, Jason Carey, Mauricio O Carneiro, Mark DePristo, Yossi Farjoun, Timothy Fennell, Jacqueline I Goldstein, George Grant, Martin Hrabé de Angelis, Jared Maguire, Benjamin M Neale, Ryan Poplin, Shaun M Purcell, Thomas Schwarzmayr, Khalid Shakir, Joshua D Smith, Tim M Strom, Thomas Wieland, Jaana Lindstrom, Ivan Brandslund, Cramer Christensen, Gabriela L Surdulescu, Timo A Lakka, Alex S F Doney, Peter Nilsson, Nicholas J. Wareham, Claudia Langenberg, Tibor V Varga, Paul W Franks, Olov Rolandsson, Anders H Rosengren, Vidya S Farook, Farook Thameem, Sobha Puppala, Satish Kumar, Donna M Lehman, Christopher P Jenkinson, Joanne E Curran, Daniel Esten Hale, Sharon P Fowler, Rector Arya, Ralph A DeFronzo, Hanna E Abboud, Ann-Christine Syvänen, Pamela J Hicks, Nicholette D Palmer, Maggie C Y Ng, Donald W Bowden, Barry I Freedman, Tonu Esko, Reedik Mägi, Lili Milani, Evelin Mihailov, Andres Metspalu, Narisu Narisu, Leena Kinnunen, Lori L Bonnycastle, Amy Swift, Dorota Pasko, Andrew R Wood, João Fadista, Toni I Pollin, Nir Barzilai, Gil Atzmon, Benjamin Glaser, Barbara Thorand, Konstantin Strauch, Annette Peters, Michael Roden, Martina Müller-Nurasyid, Liming Liang, Jennifer Kriebel, Thomas Illig, Harald Grallert, Christian Gieger, Christa Meisinger, Lars Lannfelt, Solomon K Musani, Michael Griswold, Herman A Taylor, Gregory Wilson, Adolfo Correa, Heikki Oksa, William R Scott, Uzma Afzal, Sian-Tsung Tan, Marie Loh, John C Chambers, Jobanpreet Sehmi, Jaspal Singh Kooner, Benjamin Lehne, Yoon Shin Cho, Jong-Young Lee, Bok-Ghee Han, AnneMari Käräjämäki, Qibin Qi, Lu Qi, Jinyan Huang, Frank B Hu, Olle Melander, Marju Orho-Melander, Jennifer E Below, David Aguilar, Tien Yin Wong, Jianjun Liu, Chiea-Chuen Khor, Kee Seng Chia, Wei Yen Lim, Ching-Yu Cheng, Edmund Chan, E-Shyong Tai, Tin Aung, Allan Linneberg, Bo Isomaa, Thomas Meitinger, Tiinamaija Tuomi, Liisa Hakaste, Jasmina Kravic, Marit E Jørgensen, Torsten Lauritzen, Panos Deloukas, Kathleen E Stirrups, Katharine R Owen, Andrew J Farmer, Timothy M Frayling, Stephen P O'Rahilly, Mark Walker, Jonathan C Levy, Dylan Hodgkiss, Andrew T Hattersley, Teemu Kuulasmaa, Alena Stančáková, Inês Barroso, Dwaipayan Bharadwaj, Juliana C N Chan, Giriraj R Chandak, Mark J Daly, Peter J Donnelly, Shah B Ebrahim, Paul Elliott, Tasha Fingerlin, Philippe Froguel, Cheng Hu, Weiping Jia, Ronald C W Ma, Gilean McVean, Taesung Park, Dorairaj Prabhakaran, Manjinder Sandhu, James Scott, Rob Sladek, Nikhil Tandon, Yik Ying Teo, Eleftheria Zeggini, Richard M Watanabe, Heikki A Koistinen, Y Antero Kesaniemi, Matti Uusitupa, Timothy D Spector, Veikko Salomaa, Rainer Rauramaa, Colin N A Palmer, Inga Prokopenko, Andrew D Morris, Richard N Bergman, Francis S Collins, Lars Lind, Erik Ingelsson, Jaakko Tuomilehto, Fredrik Karpe, Leif Groop, Torben Jørgensen, Torben Hansen, Oluf Pedersen, Johanna Kuusisto, Goncalo R Abecasis, Graeme I Bell, John Blangero, Nancy J Cox, Ravindranath Duggirala, Mark Seielstad, James G Wilson, Josee Dupuis, Samuli Ripatti, Craig L Hanis, Jose C Florez, Karen L Mohlke, James B Meigs, Markku Laakso, Andrew P Morris, Michael Boehnke, David Altshuler, Mark I McCarthy, Anna L Gloyn, Cecilia M Lindgren

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

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.

OriginalsprogEngelsk
TidsskriftDiabetes
Vol/bind66
Udgave nummer7
Sider (fra-til)2019-2032
ISSN0046-0192
DOI
StatusUdgivet - jul. 2017

Fingeraftryk

Type 2 Diabetes Mellitus
Fasting
Insulin
Exome
Population
Insulin Resistance
Homeostasis
Alleles
Odds Ratio
Mutation
Proteins

Citer dette

Manning, A. K., Highland, H. M., Gasser, J., Sim, X., Tukiainen, T., Fontanillas, P., ... 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(7), 2019-2032. https://doi.org/10.2337/db16-1329
Manning, Alisa K ; 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 ; 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 B ; 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 J ; 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 M ; 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, Tonu ; 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 C N ; 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, Goncalo R ; 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. I: Diabetes. 2017 ; Bind 66, Nr. 7. s. 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 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.",
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author = "Manning, {Alisa K} 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 Andrew Brown 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 B R} and Jennifer Wessel and Chu, {Audrey Y} and Scott, 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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 Tonu 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 E-Shyong Tai 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 Stanč{\'a}kov{\'a} and In{\^e}s Barroso and Dwaipayan Bharadwaj and Chan, {Juliana C N} 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 Abecasis, {Goncalo R} 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 = "{\circledC} 2017 by the American Diabetes Association.",
year = "2017",
month = "7",
doi = "10.2337/db16-1329",
language = "English",
volume = "66",
pages = "2019--2032",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association",
number = "7",

}

Manning, AK, 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, A, 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, SBR, Wessel, J, Chu, AY, Scott, RA, Goodarzi, MO, Blancher, C, Buck, G, Buck, D, Chines, PS, Gabriel, SB, Gjesing, AP, Groves, CJ, Hollensted, M, Huyghe, JR, Jackson, AU, Jun, G, Justesen, JM, Mangino, M, Murphy, J, Neville, MJ, 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, SM, 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, E-S, 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, JCN, 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, GR, 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, bind 66, nr. 7, s. 2019-2032. https://doi.org/10.2337/db16-1329

A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk. / Manning, Alisa K; 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; 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 B; 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 J; 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 M; 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, Tonu; 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 C N; 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, Goncalo R; 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.

I: Diabetes, Bind 66, Nr. 7, 07.2017, s. 2019-2032.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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 K

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

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 B R

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 B

AU - Gjesing, Anette P.

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 J

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 M

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, Tonu

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 C N

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, Goncalo R

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 - 2017/7

Y1 - 2017/7

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 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.

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.

KW - Journal Article

U2 - 10.2337/db16-1329

DO - 10.2337/db16-1329

M3 - Journal article

VL - 66

SP - 2019

EP - 2032

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 7

ER -