A Low-Frequency Inactivating Akt2 Variant Enriched in the Finnish Population is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk.

Viñuela, Ana; Wu, Ying; van de Bunt, Martijn; Wessel, Jennifer; Wieland, Thomas; Wareham, Nicholas J.; Varga, Tibor V.; Wood, Andrew R.; Wilson, Gregory; Wong, Tien Yin; Tuomi, Tiinamaija; Walker, Mark; Zeggini, Eleftheria; Watanabe, Richard M.; Uusitupa, Matti; Tuomilehto, Jaakko; Wilson, James G.; Cingolani, Pablo; Pers, Tune H.; Manning, Alisa; Brown, Andrew A.; 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; Highland, Heather M.; 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.; Eriksson, Johan G.; Jula, Antti; Gasser, Jessica; Koskinen, Seppo; Lehtimäki, Terho; Palotie, Aarno; Raitakari, Olli T.; Jacobs, Suzanne Br R.; Chu, Audrey Y.; Scott, Robert A.; Goodarzi, Mark O.; Blancher, Christine; Buck, Gemma; Buck, David; Chines, Peter S.; Gabriel, Stacey; Sim, Xueling; 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; Tukiainen, Taru; 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; Fontanillas, Pierre; Schwarzmayr, Thomas; Shakir, Khalid; Smith, Joshua D.; Strom, Tim M.; Lindstrom, Jaana; Brandslund, Ivan; Christensen, Cramer; Surdulescu, Gabriela L.; Lakka, Timo A.; Doney, Alex S. F.; Nilsson, Peter; Langenberg, Claudia; Grarup, Niels; 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; Rivas, Manuel A.; 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; Mahajan, Anubha; Narisu, Narisu; Kinnunen, Leena; Bonnycastle, Lori L.; Swift, Amy; Pasko, Dorota; Fadista, João; Pollin, Toni I.; Barzilai, Nir; Atzmon, Gil; Glaser, Benjamin; Thorand, Barbara; Strauch, Konstantin; Peters, Annette; Locke, Adam E.; 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.; 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; 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; 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.; 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; Koistinen, Heikki A.; Kesaniemi, Y. Antero; 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; 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; 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.

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Tibor Varga
Viñuela et al., 2017

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American Diabetes Association, Diabetes, 7(66), p. 2019-2032, 2017

DOI: 10.2337/db16-1329

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@article{Viñuela2017,
  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.},
  author = {Viñuela, Ana and Wu, Ying and van de Bunt, Martijn and Wessel, Jennifer and Wieland, Thomas and Wareham, Nicholas J. and Varga, Tibor V. and Wood, Andrew R. and Wilson, Gregory and Wong, Tien Yin and Tuomi, Tiinamaija and Walker, Mark and Zeggini, Eleftheria and Watanabe, Richard M. and Uusitupa, Matti and Tuomilehto, Jaakko and Wilson, James G. and Cingolani, Pablo and Pers, Tune H. and Manning, Alisa and Brown, Andrew A. and Flannick, Jason and Fuchsberger, Christian and Gamazon, Eric R. and Gaulton, Kyle J. and Im, Hae Kyung and Teslovich, Tanya M. and Blackwell, Thomas W. and Bork-Jensen, Jette and Burtt, Noël P. and Chen, Yuhui and Green, Todd and Hartl, Christopher and Highland, Heather M. and Kang, Hyun Min and Kumar, Ashish and Ladenvall, Claes and Ma, Clement and Moutsianas, Loukas and Pearson, Richard D. and Perry, John R. B. and Rayner, N. William and Robertson, Neil R. and Scott, Laura J. and Eriksson, Johan G. and Jula, Antti and Gasser, Jessica and Koskinen, Seppo and Lehtimäki, Terho and Palotie, Aarno and Raitakari, Olli T. and Jacobs, Suzanne Br R. and Chu, Audrey Y. and Scott, Robert A. and Goodarzi, Mark O. and Blancher, Christine and Buck, Gemma and Buck, David and Chines, Peter S. and Gabriel, Stacey and Sim, Xueling and Gjesing, Anette P. and Groves, Christopher J. and Hollensted, Mette and Huyghe, Jeroen R. and Jackson, Anne U. and Jun, Goo and Justesen, Johanne Marie and Mangino, Massimo and Murphy, Jacquelyn and Neville, Matt and Onofrio, Robert and Small, Kerrin S. and Stringham, Heather M. and Trakalo, Joseph and Tukiainen, Taru and Banks, Eric and Carey, Jason and Carneiro, Mauricio O. and DePristo, Mark and Farjoun, Yossi and Fennell, Timothy and Goldstein, Jacqueline I. and Grant, George and Hrabé de Angelis, Martin and Maguire, Jared and Neale, Benjamin M. and Poplin, Ryan and Purcell, Shaun and Fontanillas, Pierre and Schwarzmayr, Thomas and Shakir, Khalid and Smith, Joshua D. and Strom, Tim M. and Lindstrom, Jaana and Brandslund, Ivan and Christensen, Cramer and Surdulescu, Gabriela L. and Lakka, Timo A. and Doney, Alex S. F. and Nilsson, Peter and Langenberg, Claudia and Grarup, Niels and Franks, Paul W. and Rolandsson, Olov and Rosengren, Anders H. and Farook, Vidya S. and Thameem, Farook and Puppala, Sobha and Kumar, Satish and Lehman, Donna M. and Jenkinson, Christopher P. and Curran, Joanne E. and Hale, Daniel Esten and Fowler, Sharon P. and Arya, Rector and Rivas, Manuel A. and DeFronzo, Ralph A. and Abboud, Hanna E. and Syvänen, Ann-Christine and Hicks, Pamela J. and Palmer, Nicholette D. and Ng, Maggie C. Y. and Bowden, Donald W. and Freedman, Barry I. and Esko, Tõnu and Mägi, Reedik and Milani, Lili and Mihailov, Evelin and Metspalu, Andres and Mahajan, Anubha and Narisu, Narisu and Kinnunen, Leena and Bonnycastle, Lori L. and Swift, Amy and Pasko, Dorota and Fadista, João and Pollin, Toni I. and Barzilai, Nir and Atzmon, Gil and Glaser, Benjamin and Thorand, Barbara and Strauch, Konstantin and Peters, Annette and Locke, Adam E. and Roden, Michael and Müller-Nurasyid, Martina and Liang, Liming and Kriebel, Jennifer and Illig, Thomas and Grallert, Harald and Gieger, Christian and Meisinger, Christa and Lannfelt, Lars and Musani, Solomon K. and Griswold, Michael and Taylor, Herman A. and Correa, Adolfo and Oksa, Heikki and Scott, William R. and Afzal, Uzma and Tan, Sian-Tsung and Loh, Marie and Chambers, John C. and Sehmi, Jobanpreet and Kooner, Jaspal Singh and Lehne, Benjamin and Cho, Yoon Shin and Lee, Jong-Young and Han, Bok-Ghee and Käräjämäki, Annemari and Qi, Qibin and Qi, Lu and Huang, Jinyan and Hu, Frank B. and Melander, Olle and Orho-Melander, Marju and Below, Jennifer E. and Aguilar, David and Liu, Jianjun and Khor, Chiea-Chuen and Chia, Kee Seng and Lim, Wei Yen and Cheng, Ching-Yu and Chan, Edmund and Tai, E. Shyong and Aung, Tin and Linneberg, Allan and Isomaa, Bo and Meitinger, Thomas and Hakaste, Liisa and Kravic, Jasmina and Jørgensen, Marit E. and Lauritzen, Torsten and Deloukas, Panos and Stirrups, Kathleen E. and Owen, Katharine R. and Farmer, Andrew J. and Frayling, Timothy M. and O'Rahilly, Stephen P. and Levy, Jonathan C. and Hodgkiss, Dylan and Hattersley, Andrew T. and Kuulasmaa, Teemu and Stančáková, Alena and Barroso, Inês and Bharadwaj, Dwaipayan and Chan, Juliana and Chandak, Giriraj R. and Daly, Mark J. and Donnelly, Peter J. and Ebrahim, Shah B. and Elliott, Paul and Fingerlin, Tasha and Froguel, Philippe and Hu, Cheng and Jia, Weiping and Ma, Ronald C. W. and McVean, Gilean and Park, Taesung and Prabhakaran, Dorairaj and Sandhu, Manjinder and Scott, James and Sladek, Rob and Tandon, Nikhil and Teo, Yik Ying and Koistinen, Heikki A. and Kesaniemi, Y. Antero and Spector, Timothy D. and Salomaa, Veikko and Rauramaa, Rainer and Palmer, Colin N. A. and Prokopenko, Inga and Morris, Andrew D. and Bergman, Richard N. and Collins, Francis S. and Lind, Lars and Ingelsson, Erik and Karpe, Fredrik and Groop, Leif and Jørgensen, Torben and Hansen, Torben and Pedersen, Oluf and Kuusisto, Johanna and Abecasis, Gonçalo and Bell, Graeme I. and Blangero, John and Cox, Nancy J. and Duggirala, Ravindranath and Seielstad, Mark and Dupuis, Josee and Ripatti, Samuli and Hanis, Craig L. and Florez, Jose C. and Mohlke, Karen L. and Meigs, James B. and Laakso, Markku and Morris, Andrew P. and Boehnke, Michael and Altshuler, David and McCarthy, Mark I. and Gloyn, Anna L. and Lindgren, Cecilia M.},
  doi = {10.2337/db16-1329},
  journal = {Diabetes},
  month = {mar},
  pages = {2019-2032},
  title = { A Low-Frequency Inactivating Akt2 Variant Enriched in the Finnish Population is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk. },
  url = {https://journals.org/diabetes/diabetes/article-pdf/66/7/2019/537733/db161329.pdf},
  volume = {66},
  year = {2017}
}

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A Low-Frequency Inactivating Akt2 Variant Enriched in the Finnish Population is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk.

Journal article published in 2017 by Ana Viñuela, Ying Wu, Martijn van de Bunt, Jennifer Wessel, Thomas Wieland, Nicholas J. Wareham, Tibor V. Varga

, Andrew R. Wood, Gregory Wilson, Tien Yin Wong, Tiinamaija Tuomi, Mark Walker, Eleftheria Zeggini, Richard M. Watanabe, Matti Uusitupa and other authors. Ana Viñuela, Ying Wu, Martijn van de Bunt, Jennifer Wessel, Thomas Wieland, Nicholas J. Wareham, Tibor V. Varga

, Andrew R. Wood, Gregory Wilson, Tien Yin Wong, Tiinamaija Tuomi, Mark Walker, Eleftheria Zeggini, Richard M. Watanabe, Matti Uusitupa, Jaakko Tuomilehto, James G. Wilson, Pablo Cingolani, Tune H. Pers, Alisa Manning, Andrew A. Brown, Jason Flannick, Christian Fuchsberger, Eric R. Gamazon, Kyle J. Gaulton, Hae Kyung Im, Tanya M. Teslovich, Thomas W. Blackwell, Jette Bork-Jensen

, Noël P. Burtt, Yuhui Chen, Todd Green, Christopher Hartl, Heather M. Highland, 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, Johan G. Eriksson, Antti Jula, Jessica Gasser, Seppo Koskinen, Terho Lehtimäki, Aarno Palotie, Olli T. Raitakari, Suzanne Br R. Jacobs, Audrey Y. Chu, Robert A. Scott, Mark O. Goodarzi, Christine Blancher, Gemma Buck

, David Buck, Peter S. Chines, Stacey Gabriel, Xueling Sim, Anette P. Gjesing, Christopher J. Groves, Mette Hollensted, Jeroen R. Huyghe, Anne U. Jackson, Goo Jun, Johanne Marie Justesen

, Massimo Mangino, Jacquelyn Murphy, Matt Neville, Robert Onofrio, Kerrin S. Small, Heather M. Stringham, Joseph Trakalo, Taru Tukiainen, 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 Purcell, Pierre Fontanillas, Thomas Schwarzmayr, Khalid Shakir, Joshua D. Smith, Tim M. Strom, Jaana Lindstrom

, Ivan Brandslund

, Cramer Christensen, Gabriela L. Surdulescu, Timo A. Lakka, Alex S. F. Doney, Peter Nilsson, Claudia Langenberg, Niels Grarup, 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, Manuel A. Rivas, 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, Tõnu Esko, Reedik Mägi

, Lili Milani, Evelin Mihailov, Andres Metspalu, Anubha Mahajan, Narisu Narisu, Leena Kinnunen, Lori L. Bonnycastle, Amy Swift, Dorota Pasko, João Fadista

, Toni I. Pollin, Nir Barzilai, Gil Atzmon, Benjamin Glaser, Barbara Thorand, Konstantin Strauch, Annette Peters, Adam E. Locke, 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, 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, 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, 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, Jonathan C. Levy, Dylan Hodgkiss, Andrew T. Hattersley, Teemu Kuulasmaa, Alena Stančáková, Inês Barroso, Dwaipayan Bharadwaj, Juliana 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, Heikki A. Koistinen, Y. Antero Kesaniemi, 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, Fredrik Karpe, Leif Groop, Torben Jørgensen, Torben Hansen, Oluf Pedersen, Johanna Kuusisto, Gonçalo Abecasis, Graeme I. Bell, John Blangero, Nancy J. Cox, Ravindranath Duggirala, Mark Seielstad, 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

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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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A Low-Frequency Inactivating Akt2 Variant Enriched in the Finnish Population is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk.

Abstract