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 R.; 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; 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.

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Claes Ladenvall
Manning 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{Manning2017,
  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 = {Manning, Alisa and Highland, Heather M. and Gasser, Jessica and Sim, Xueling and Tukiainen, Taru and Fontanillas, Pierre and Grarup, Niels and Rivas, Manuel A. and Mahajan, Anubha and Locke, Adam E. and Cingolani, Pablo and Pers, Tune H. and Viñuela, Ana and Brown, Andrew A. and Wu, Ying 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 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 van de Bunt, Martijn and Eriksson, Johan G. and Jula, Antti and Koskinen, Seppo and Lehtimäki, Terho and Palotie, Aarno and Raitakari, Olli T. and Jacobs, Suzanne Br R. and Wessel, Jennifer 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 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 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 Schwarzmayr, Thomas and Shakir, Khalid and Smith, Joshua D. and Strom, Tim M. and Wieland, Thomas 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 Wareham, Nicholas J. and Langenberg, Claudia and Varga, Tibor V. 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 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 Narisu, Narisu and Kinnunen, Leena and Bonnycastle, Lori L. and Swift, Amy and Pasko, Dorota and Wood, Andrew R. 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 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 Wilson, Gregory 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 Wong, Tien Yin 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 Tuomi, Tiinamaija 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 Walker, Mark 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 Zeggini, Eleftheria and Watanabe, Richard M. and Koistinen, Heikki A. and Kesaniemi, Y. Antero and Uusitupa, Matti 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 Tuomilehto, Jaakko 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 Wilson, James G. 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 Alisa 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 A. Brown, Ying Wu and other authors. Alisa 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 A. Brown, Ying Wu, 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, 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 Br R. Jacobs, Jennifer Wessel, Audrey Y. Chu, Robert A. Scott, Mark O. Goodarzi, Christine Blancher, Gemma Buck, David Buck, Peter S. Chines, Stacey 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 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 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, Tõnu 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 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, Gonçalo 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

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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