A low-frequency inactivating AKT2 variant enriched in the finnish population is associated with fasting insulin levels and type 2 diabetes risk

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 B.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; Ol L. E Mel Ander; Marju Orho-Melander; Jennifer E. Below; David Aguilar; Tien Yin Wong; Jianjun Li U; 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; Jasmi Na Kravi C; Marit E. Jørgensen; Torsten Lauritzen; Panos Deloukas; Kathleen E. Stirrups; Kat Har Kat; Andrew J. Farmer; Timothy M. Frayling; Stephen P. O’rahilly; Mark Walker; Jonathan C. Levy; Dylan Hodgkiss; Andrew T. Hattersley; Teemu Kuulasmaa; Alena Stan?cáková; 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

doi: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

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 ImTanya 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 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, Ol L. E Mel Ander, Marju Orho-Melander, Jennifer E. Below, David Aguilar, Tien Yin Wong, Jianjun Li U, 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, Jasmi Na Kravi C, Marit E. Jørgensen, Torsten Lauritzen, Panos Deloukas, Kathleen E. Stirrups, Kat Har Kat, Andrew J. Farmer, Timothy M. Frayling, Stephen P. O’rahilly, Mark Walker, Jonathan C. Levy, Dylan Hodgkiss, Andrew T. Hattersley, Teemu Kuulasmaa, Alena Stan?cáková, 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

Internal Medicine

Research output: Contribution to journal › Article › peer-review

40 Scopus citations

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.

Original language	English
Pages (from-to)	2019-2032
Number of pages	14
Journal	Diabetes
Volume	66
Issue number	7
DOIs	https://doi.org/10.2337/db16-1329
State	Published - Jul 1 2017

Bibliographical note

Publisher Copyright:
© 2017 by the American Diabetes Association.

Funding

The authors acknowledge the following funding sources: Academy of Finland (102318, 129293, 128315, 129330, 131593, 139635, 121584, 126925, 124282, 129378, 258753, 123885, 124243); Action on Hearing Loss (G51); Jalmari and Rauha Ahokas Foundation; American Diabetes Association (7-12-MN-02); Archimedes Foundation (3.2.1001.11-0033); Atlantic Canada Opportunities Agency; Augustinus Foundation; Becket Foundation; Alfred Benzon Foundation; Biomedical Research Council; British Heart Foundation (SP/04/002); Canada Foundation for Innovation; City of Kuopio and Social Insurance Institution of Finland (4/26/2010);

Funders	Funder number
Becket Foundation
American Diabetes Association Inc	7-12-MN-02
American Diabetes Association Inc
National Human Genome Research Institute	ZIAHG000024
National Human Genome Research Institute
Sihtasutus Archimedes	3.2.1001.11-0033
Sihtasutus Archimedes
Jalmari ja Rauha Ahokkaan Säätiö
Canada Foundation for Innovation	4/26/2010
Canada Foundation for Innovation
British Heart Foundation	SP/04/002
British Heart Foundation
Academy of Finland	129330, G51, 131593, 129378, 139635, 124243, 129293, 124282, 126925, 121584, 123885, 258753, 128315, 102318
Academy of Finland
Atlantic Canada Opportunities Agency
Augustinus Fonden
Alfred Benzon Foundation
College Research Council of the College of Veterinary Medicine and Biomedical Sciences

ASJC Scopus subject areas

Internal Medicine
Endocrinology, Diabetes and Metabolism

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.2337/db16-1329

Cite this

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(7), 2019-2032. https://doi.org/10.2337/db16-1329

@article{f5655d8eed7e45e9b32f5831b0138c6c,

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 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 = "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 B.R.} 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 P.} 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 {de Angelis}, {Martin Hrab{\'e}} 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 Syv{\"a}nen, {Ann Christine} 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 Tan, {Sian Tsung} and Marie Loh and Chambers, {John C.} and Jobanpreet Sehmi and Kooner, {Jaspal Singh} and Benjamin Lehne and Cho, {Yoon Shin} and Lee, {Jong Young} and Han, {Bok Ghee} 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 {E Mel Ander}, {Ol L.} and Marju Orho-Melander and Below, {Jennifer E.} and David Aguilar and Wong, {Tien Yin} and U, {Jianjun Li} and Khor, {Chiea Chuen} and Chia, {Kee Seng} and Lim, {Wei Yen} and Cheng, {Ching Yu} and Edmund Chan and {Shyong Tai}, E. and Tin Aung and Allan Linneberg and Bo Isomaa and Thomas Meitinger and Tiinamaija Tuomi and Liisa Hakaste and {Na Kravi C}, Jasmi and J{\o}rgensen, {Marit E.} and Torsten Lauritzen and Panos Deloukas and Stirrups, {Kathleen E.} and Kat, {Kat Har} and Farmer, {Andrew J.} and Frayling, {Timothy M.} and O{\textquoteright}rahilly, {Stephen P.} and Mark Walker and Levy, {Jonathan C.} and Dylan Hodgkiss and Hattersley, {Andrew T.} and Teemu Kuulasmaa and Alena Stan?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 {Antero Kesaniemi}, Y. 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 = "Publisher Copyright: {\textcopyright} 2017 by the American Diabetes Association.",

year = "2017",

month = jul,

day = "1",

doi = "10.2337/db16-1329",

language = "English",

volume = "66",

pages = "2019--2032",

number = "7",

}

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, SBR, Wessel, J, Chu, AY, Scott, RA, Goodarzi, MO, Blancher, C, Buck, G, Buck, D, Chines, PS, Gabriel, S, Gjesing, AP, 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, de Angelis, MH, 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, AC, 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, ST, Loh, M, Chambers, JC, Sehmi, J, Kooner, JS, Lehne, B, Cho, YS, Lee, JY, Han, BG, Käräjämäki, A, Qi, Q, Qi, L, Huang, J, Hu, FB, E Mel Ander, OL, Orho-Melander, M, Below, JE, Aguilar, D, Wong, TY, U, JL, Khor, CC, Chia, KS, Lim, WY, Cheng, CY, Chan, E, Shyong Tai, E, Aung, T, Linneberg, A, Isomaa, B, Meitinger, T, Tuomi, T, Hakaste, L, Na Kravi C, J, Jørgensen, ME, Lauritzen, T, Deloukas, P, Stirrups, KE, Kat, KH, Farmer, AJ, Frayling, TM, O’rahilly, SP, Walker, M, Levy, JC, Hodgkiss, D, Hattersley, AT, Kuulasmaa, T, Stan?cáková, 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, Antero Kesaniemi, Y, 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, no. 7, pp. 2019-2032. https://doi.org/10.2337/db16-1329

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 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

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

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 - de Angelis, Martin Hrabé

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 - E Mel Ander, Ol L.

AU - Orho-Melander, Marju

AU - Below, Jennifer E.

AU - Aguilar, David

AU - Wong, Tien Yin

AU - U, Jianjun Li

AU - Khor, Chiea Chuen

AU - Chia, Kee Seng

AU - Lim, Wei Yen

AU - Cheng, Ching Yu

AU - Chan, Edmund

AU - Shyong Tai, E.

AU - Aung, Tin

AU - Linneberg, Allan

AU - Isomaa, Bo

AU - Meitinger, Thomas

AU - Tuomi, Tiinamaija

AU - Hakaste, Liisa

AU - Na Kravi C, Jasmi

AU - Jørgensen, Marit E.

AU - Lauritzen, Torsten

AU - Deloukas, Panos

AU - Stirrups, Kathleen E.

AU - Kat, Kat Har

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 - Stan?cáková, 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 - Antero Kesaniemi, Y.

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.

PY - 2017/7/1

Y1 - 2017/7/1

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.

UR - http://www.scopus.com/inward/record.url?scp=85021073183&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85021073183&partnerID=8YFLogxK

U2 - 10.2337/db16-1329

DO - 10.2337/db16-1329

M3 - Article

C2 - 28341696

AN - SCOPUS:85021073183

SN - 0012-1797

VL - 66

SP - 2019

EP - 2032

JO - Diabetes

JF - Diabetes

IS - 7

ER -

A low-frequency inactivating AKT2 variant enriched in the finnish population is associated with fasting insulin levels and type 2 diabetes risk

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this