Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis

Benjamin F. Voight; Laura J. Scott; Valgerdur Steinthorsdottir; Andrew P. Morris; Christian Dina; Ryan P. Welch; Eleftheria Zeggini; Cornelia Huth; Yurii S. Aulchenko; Gudmar Thorleifsson; Laura J. McCulloch; Teresa Ferreira; Harald Grallert; Najaf Amin; Guanming Wu; Cristen J. Willer; Soumya Raychaudhuri; Steve A. McCarroll; Claudia Langenberg; Oliver M. Hofmann; Josée Dupuis; Lu Qi; Ayellet V. Segrè; Mandy Van Hoek; Pau Navarro; Kristin Ardlie; Beverley Balkau; Rafn Benediktsson; Amanda J. Bennett; Roza Blagieva; Eric Boerwinkle; Lori L. Bonnycastle; Kristina Bengtsson Boström; Bert Bravenboer; Suzannah Bumpstead; Noisël P. Burtt; Guillaume Charpentier; Peter S. Chines; Marilyn Cornelis; David J. Couper; Gabe Crawford; Alex S F Doney; Katherine S. Elliott; Amanda L. Elliott; Michael R. Erdos; Caroline S. Fox; Christopher S. Franklin; Martha Ganser; Christian Gieger; Niels Grarup; Todd Green; Simon Griffin; Christopher J. Groves; Candace Guiducci; Samy Hadjadj; Neelam Hassanali; Christian Herder; Bo Isomaa; Anne U. Jackson; Paul R V Johnson; Torben Jørgensen; Wen H L Kao; Norman Klopp; Augustine Kong; Peter Kraft; Johanna Kuusisto; Torsten Lauritzen; Man Li; Aloysius Lieverse; Cecilia M. Lindgren; Valeriya Lyssenko; Michel Marre; Thomas Meitinger; Kristian Midthjell; Mario A. Morken; Narisu Narisu; Peter Nilsson; Katharine R. Owen; Felicity Payne; John R B Perry; Ann Kristin Petersen; Carl Platou; Christine Proença; Inga Prokopenko; Wolfgang Rathmann; N. William Rayner; Neil R. Robertson; Ghislain Rocheleau; Michael Roden; Michael J. Sampson; Richa Saxena; Beverley M. Shields; Peter Shrader; Gunnar Sigurdsson; Thomas Sparsø; Klaus Strassburger; Heather M. Stringham; Qi Sun; Amy J. Swift; Barbara Thorand; Jean Tichet; Tiinamaija Tuomi; Rob M. Van Dam; Timon W. Van Haeften; Thijs Van Herpt; Jana V. Van Vliet-Ostaptchouk; G. Bragi Walters; Michael N. Weedon; Cisca Wijmenga; Jacqueline Witteman; Richard N. Bergman; Stephane Cauchi; Francis S. Collins; Anna L. Gloyn; Ulf Gyllensten; Torben Hansen; Winston A. Hide; Graham A. Hitman; Albert Hofman; David J. Hunter; Kristian Hveem; Markku Laakso; Karen L. Mohlke; Andrew D. Morris; Colin N A Palmer; Peter P. Pramstaller; Igor Rudan; Eric Sijbrands; Lincoln D. Stein; Jaakko Tuomilehto; Andre Uitterlinden; Mark Walker; Nicholas J. Wareham; Richard M. Watanabe; Gonçalo R. Abecasis; Bernhard O. Boehm; Harry Campbell; Mark J. Daly; Andrew T. Hattersley; Frank B. Hu; James B. Meigs; James S. Pankow; Oluf Pedersen; H. Erich Wichmann; Inês Barroso; Jose C. Florez; Timothy M. Frayling; Leif Groop; Rob Sladek; Unnur Thorsteinsdottir; James F. Wilson; Thomas Illig; Philippe Froguel; Cornelia M. Van Duijn; Kari Stefansson; David Altshuler; Michael Boehnke; Mark I. McCarthy

doi:10.1038/ng.609

Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis

Benjamin F. Voight, Laura J. Scott, Valgerdur Steinthorsdottir, Andrew P. Morris, Christian Dina, Ryan P. Welch, Eleftheria Zeggini, Cornelia Huth, Yurii S. Aulchenko, Gudmar Thorleifsson, Laura J. McCulloch, Teresa Ferreira, Harald Grallert, Najaf Amin, Guanming Wu, Cristen J. Willer, Soumya Raychaudhuri, Steve A. McCarroll, Claudia Langenberg, Oliver M. HofmannJosée Dupuis, Lu Qi, Ayellet V. Segrè, Mandy Van Hoek, Pau Navarro, Kristin Ardlie, Beverley Balkau, Rafn Benediktsson, Amanda J. Bennett, Roza Blagieva, Eric Boerwinkle, Lori L. Bonnycastle, Kristina Bengtsson Boström, Bert Bravenboer, Suzannah Bumpstead, Noisël P. Burtt, Guillaume Charpentier, Peter S. Chines, Marilyn Cornelis, David J. Couper, Gabe Crawford, Alex S F Doney, Katherine S. Elliott, Amanda L. Elliott, Michael R. Erdos, Caroline S. Fox, Christopher S. Franklin, Martha Ganser, Christian Gieger, Niels Grarup, Todd Green, Simon Griffin, Christopher J. Groves, Candace Guiducci, Samy Hadjadj, Neelam Hassanali, Christian Herder, Bo Isomaa, Anne U. Jackson, Paul R V Johnson, Torben Jørgensen, Wen H L Kao, Norman Klopp, Augustine Kong, Peter Kraft, Johanna Kuusisto, Torsten Lauritzen, Man Li, Aloysius Lieverse, Cecilia M. Lindgren, Valeriya Lyssenko, Michel Marre, Thomas Meitinger, Kristian Midthjell, Mario A. Morken, Narisu Narisu, Peter Nilsson, Katharine R. Owen, Felicity Payne, John R B Perry, Ann Kristin Petersen, Carl Platou, Christine Proença, Inga Prokopenko, Wolfgang Rathmann, N. William Rayner, Neil R. Robertson, Ghislain Rocheleau, Michael Roden, Michael J. Sampson, Richa Saxena, Beverley M. Shields, Peter Shrader, Gunnar Sigurdsson, Thomas Sparsø, Klaus Strassburger, Heather M. Stringham, Qi Sun, Amy J. Swift, Barbara Thorand, Jean Tichet, Tiinamaija Tuomi, Rob M. Van Dam, Timon W. Van Haeften, Thijs Van Herpt, Jana V. Van Vliet-Ostaptchouk, G. Bragi Walters, Michael N. Weedon, Cisca Wijmenga, Jacqueline Witteman, Richard N. Bergman, Stephane Cauchi, Francis S. Collins, Anna L. Gloyn, Ulf Gyllensten, Torben Hansen, Winston A. Hide, Graham A. Hitman, Albert Hofman, David J. Hunter, Kristian Hveem, Markku Laakso, Karen L. Mohlke, Andrew D. Morris, Colin N A Palmer, Peter P. Pramstaller, Igor Rudan, Eric Sijbrands, Lincoln D. Stein, Jaakko Tuomilehto, Andre Uitterlinden, Mark Walker, Nicholas J. Wareham, Richard M. Watanabe, Gonçalo R. Abecasis, Bernhard O. Boehm, Harry Campbell, Mark J. Daly, Andrew T. Hattersley, Frank B. Hu, James B. Meigs, James S. Pankow, Oluf Pedersen, H. Erich Wichmann, Inês Barroso, Jose C. Florez, Timothy M. Frayling, Leif Groop, Rob Sladek, Unnur Thorsteinsdottir, James F. Wilson, Thomas Illig, Philippe Froguel, Cornelia M. Van Duijn, Kari Stefansson, David Altshuler, Michael Boehnke, Mark I. McCarthy

Epidemiology

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

1482 Scopus citations

Abstract

By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P 5 × 10 8. These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits.

Original language	English (US)
Pages (from-to)	579-589
Number of pages	11
Journal	Nature Genetics
Volume	42
Issue number	7
DOIs	https://doi.org/10.1038/ng.609
State	Published - Jul 2010

Bibliographical note

Funding Information:
We acknowledge funding from: the Academy of Finland (no. 124243); Agence Nationale de la Recherche (France); American Diabetes Association (1-05-RA-140, 7-08-MN-OK; 7-06-MN-05); Ardix Medical; Association Diabète Risque Vasculaire; Association de Langue Française pour l’Etude du Diabète et des Maladies Métaboliques; Association Française des Diabétiques; Bayer Diagnostics; British Diabetic Association Research; Becton Dickinson; Broad Institute of Harvard and Massachusetts Institute of Technology; The Burroughs Wellcome Fund; Cardionics; Center for Inherited Disease Research (USA); Centre for Medical Systems Biology (The Netherlands); Centre of Excellence Metabolic Disorders Baden-Wuerttemberg (Germany); Caisse Nationale Assurance Maladie des Travailleurs Salariés (France); Clinical Research Institute HUCH Ltd; Deutsche Forschungsgemeinschaft (DFG GrK 1041, DFG RA459, SFB 518); the Danish Diabetes Association; the Danish Health Research Council; Diabetes UK; Doris Duke Charitable Foundation; Erasmus Medical Center (The Netherlands); the Dutch Diabetes Foundation; European Community (HEALTH-F4-2007-201413, HEALTH-2007-B-223211, LSHG-CT-2006-01947, LSHM-CT-2004-512013, LSHM-CT-2004-005272, LSHM-CT-2006-518153); the European Foundation for the Study of Diabetes; the Federal Ministry of Health (Germany); the Federal Ministry of Education and Research (Germany) (FKZ01GS0823 and DZD e.V.); Fédération Française de Cardiologie; The Finnish Diabetes Research Foundation; The Folkhalsan Research Foundation; The Foundation for Strategic Research (Sweden); The Foundation of Bristol-Myers Squibb; the German National Genome Research Network; Helmholtz Zentrum München-Research Center for Environment and Health; INSERM (France); La Fondation de France; Lilly; The Linnaeus Centre for Bioinformatics (Sweden); the Lundbeck Foundation Centre of Applied Medical Genomics for Personalized Disease Prediction, Prevention and Care; the Medical Research Council UK (G0601261, G0000649; 081696); Munich Center of Health Sciences-LMU Innovativ (Germany); Merck Santé; the Ministry of Health and Department of Educational Assistance, University and Research of the Autonomous Province of Bolzano (Italy); the Ministry of Innovation, Science, Research and Technology of the State of North Rhine-Westphalia (Germany); the Ministry of Science, Education and Sport (Croatia); the National Heart, Lung, and Blood Institute (N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, N01-HC-25195, R01HL087641, R01HL59367, R01HL086694, N02-HL-6-4278); National Human Genome Research Institute (U01HG004402, U01HG004399, U01HG004171, 1 Z01 HG000024); the National Institute of Diabetes, Digestive and Kidney Diseases (DK078616, K24-DK080140, U54 DA021519, DK58845, DK069922, DK062370, DK073490, K23-DK65978 and DK072193); the US National Institutes of Health (HHSN268200625226C, HHSN268200625226C, 1K08AR055688, UL1RR025005, 1K99HL094535-01A1); the Netherlands Foundation for Scientific Research (175.010.2005.011, 047.017.043);

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Voight, B. F., Scott, L. J., Steinthorsdottir, V., Morris, A. P., Dina, C., Welch, R. P., Zeggini, E., Huth, C., Aulchenko, Y. S., Thorleifsson, G., McCulloch, L. J., Ferreira, T., Grallert, H., Amin, N., Wu, G., Willer, C. J., Raychaudhuri, S., McCarroll, S. A., Langenberg, C., ... McCarthy, M. I. (2010). Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nature Genetics, 42(7), 579-589. https://doi.org/10.1038/ng.609

Voight, BF, Scott, LJ, Steinthorsdottir, V, Morris, AP, Dina, C, Welch, RP, Zeggini, E, Huth, C, Aulchenko, YS, Thorleifsson, G, McCulloch, LJ, Ferreira, T, Grallert, H, Amin, N, Wu, G, Willer, CJ, Raychaudhuri, S, McCarroll, SA, Langenberg, C, Hofmann, OM, Dupuis, J, Qi, L, Segrè, AV, Van Hoek, M, Navarro, P, Ardlie, K, Balkau, B, Benediktsson, R, Bennett, AJ, Blagieva, R, Boerwinkle, E, Bonnycastle, LL, Boström, KB, Bravenboer, B, Bumpstead, S, Burtt, NP, Charpentier, G, Chines, PS, Cornelis, M, Couper, DJ, Crawford, G, Doney, ASF, Elliott, KS, Elliott, AL, Erdos, MR, Fox, CS, Franklin, CS, Ganser, M, Gieger, C, Grarup, N, Green, T, Griffin, S, Groves, CJ, Guiducci, C, Hadjadj, S, Hassanali, N, Herder, C, Isomaa, B, Jackson, AU, Johnson, PRV, Jørgensen, T, Kao, WHL, Klopp, N, Kong, A, Kraft, P, Kuusisto, J, Lauritzen, T, Li, M, Lieverse, A, Lindgren, CM, Lyssenko, V, Marre, M, Meitinger, T, Midthjell, K, Morken, MA, Narisu, N, Nilsson, P, Owen, KR, Payne, F, Perry, JRB, Petersen, AK, Platou, C, Proença, C, Prokopenko, I, Rathmann, W, Rayner, NW, Robertson, NR, Rocheleau, G, Roden, M, Sampson, MJ, Saxena, R, Shields, BM, Shrader, P, Sigurdsson, G, Sparsø, T, Strassburger, K, Stringham, HM, Sun, Q, Swift, AJ, Thorand, B, Tichet, J, Tuomi, T, Van Dam, RM, Van Haeften, TW, Van Herpt, T, Van Vliet-Ostaptchouk, JV, Walters, GB, Weedon, MN, Wijmenga, C, Witteman, J, Bergman, RN, Cauchi, S, Collins, FS, Gloyn, AL, Gyllensten, U, Hansen, T, Hide, WA, Hitman, GA, Hofman, A, Hunter, DJ, Hveem, K, Laakso, M, Mohlke, KL, Morris, AD, Palmer, CNA, Pramstaller, PP, Rudan, I, Sijbrands, E, Stein, LD, Tuomilehto, J, Uitterlinden, A, Walker, M, Wareham, NJ, Watanabe, RM, Abecasis, GR, Boehm, BO, Campbell, H, Daly, MJ, Hattersley, AT, Hu, FB, Meigs, JB, Pankow, JS, Pedersen, O, Wichmann, HE, Barroso, I, Florez, JC, Frayling, TM, Groop, L, Sladek, R, Thorsteinsdottir, U, Wilson, JF, Illig, T, Froguel, P, Van Duijn, CM, Stefansson, K, Altshuler, D, Boehnke, M & McCarthy, MI 2010, 'Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis', Nature Genetics, vol. 42, no. 7, pp. 579-589. https://doi.org/10.1038/ng.609

@article{ee0bb31bae8748e998618f8bbe47ff9e,

title = "Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis",

abstract = "By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P 5 × 10 8. These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits.",

author = "Voight, {Benjamin F.} and Scott, {Laura J.} and Valgerdur Steinthorsdottir and Morris, {Andrew P.} and Christian Dina and Welch, {Ryan P.} and Eleftheria Zeggini and Cornelia Huth and Aulchenko, {Yurii S.} and Gudmar Thorleifsson and McCulloch, {Laura J.} and Teresa Ferreira and Harald Grallert and Najaf Amin and Guanming Wu and Willer, {Cristen J.} and Soumya Raychaudhuri and McCarroll, {Steve A.} and Claudia Langenberg and Hofmann, {Oliver M.} and Jos{\'e}e Dupuis and Lu Qi and Segr{\`e}, {Ayellet V.} and {Van Hoek}, Mandy and Pau Navarro and Kristin Ardlie and Beverley Balkau and Rafn Benediktsson and Bennett, {Amanda J.} and Roza Blagieva and Eric Boerwinkle and Bonnycastle, {Lori L.} and Bostr{\"o}m, {Kristina Bengtsson} and Bert Bravenboer and Suzannah Bumpstead and Burtt, {Nois{\"e}l P.} and Guillaume Charpentier and Chines, {Peter S.} and Marilyn Cornelis and Couper, {David J.} and Gabe Crawford and Doney, {Alex S F} and Elliott, {Katherine S.} and Elliott, {Amanda L.} and Erdos, {Michael R.} and Fox, {Caroline S.} and Franklin, {Christopher S.} and Martha Ganser and Christian Gieger and Niels Grarup and Todd Green and Simon Griffin and Groves, {Christopher J.} and Candace Guiducci and Samy Hadjadj and Neelam Hassanali and Christian Herder and Bo Isomaa and Jackson, {Anne U.} and Johnson, {Paul R V} and Torben J{\o}rgensen and Kao, {Wen H L} and Norman Klopp and Augustine Kong and Peter Kraft and Johanna Kuusisto and Torsten Lauritzen and Man Li and Aloysius Lieverse and Lindgren, {Cecilia M.} and Valeriya Lyssenko and Michel Marre and Thomas Meitinger and Kristian Midthjell and Morken, {Mario A.} and Narisu Narisu and Peter Nilsson and Owen, {Katharine R.} and Felicity Payne and Perry, {John R B} and Petersen, {Ann Kristin} and Carl Platou and Christine Proen{\c c}a and Inga Prokopenko and Wolfgang Rathmann and Rayner, {N. William} and Robertson, {Neil R.} and Ghislain Rocheleau and Michael Roden and Sampson, {Michael J.} and Richa Saxena and Shields, {Beverley M.} and Peter Shrader and Gunnar Sigurdsson and Thomas Spars{\o} and Klaus Strassburger and Stringham, {Heather M.} and Qi Sun and Swift, {Amy J.} and Barbara Thorand and Jean Tichet and Tiinamaija Tuomi and {Van Dam}, {Rob M.} and {Van Haeften}, {Timon W.} and {Van Herpt}, Thijs and {Van Vliet-Ostaptchouk}, {Jana V.} and Walters, {G. Bragi} and Weedon, {Michael N.} and Cisca Wijmenga and Jacqueline Witteman and Bergman, {Richard N.} and Stephane Cauchi and Collins, {Francis S.} and Gloyn, {Anna L.} and Ulf Gyllensten and Torben Hansen and Hide, {Winston A.} and Hitman, {Graham A.} and Albert Hofman and Hunter, {David J.} and Kristian Hveem and Markku Laakso and Mohlke, {Karen L.} and Morris, {Andrew D.} and Palmer, {Colin N A} and Pramstaller, {Peter P.} and Igor Rudan and Eric Sijbrands and Stein, {Lincoln D.} and Jaakko Tuomilehto and Andre Uitterlinden and Mark Walker and Wareham, {Nicholas J.} and Watanabe, {Richard M.} and Abecasis, {Gon{\c c}alo R.} and Boehm, {Bernhard O.} and Harry Campbell and Daly, {Mark J.} and Hattersley, {Andrew T.} and Hu, {Frank B.} and Meigs, {James B.} and Pankow, {James S.} and Oluf Pedersen and Wichmann, {H. Erich} and In{\^e}s Barroso and Florez, {Jose C.} and Frayling, {Timothy M.} and Leif Groop and Rob Sladek and Unnur Thorsteinsdottir and Wilson, {James F.} and Thomas Illig and Philippe Froguel and {Van Duijn}, {Cornelia M.} and Kari Stefansson and David Altshuler and Michael Boehnke and McCarthy, {Mark I.}",

note = "Funding Information: We acknowledge funding from: the Academy of Finland (no. 124243); Agence Nationale de la Recherche (France); American Diabetes Association (1-05-RA-140, 7-08-MN-OK; 7-06-MN-05); Ardix Medical; Association Diab{\`e}te Risque Vasculaire; Association de Langue Fran{\c c}aise pour l{\textquoteright}Etude du Diab{\`e}te et des Maladies M{\'e}taboliques; Association Fran{\c c}aise des Diab{\'e}tiques; Bayer Diagnostics; British Diabetic Association Research; Becton Dickinson; Broad Institute of Harvard and Massachusetts Institute of Technology; The Burroughs Wellcome Fund; Cardionics; Center for Inherited Disease Research (USA); Centre for Medical Systems Biology (The Netherlands); Centre of Excellence Metabolic Disorders Baden-Wuerttemberg (Germany); Caisse Nationale Assurance Maladie des Travailleurs Salari{\'e}s (France); Clinical Research Institute HUCH Ltd; Deutsche Forschungsgemeinschaft (DFG GrK 1041, DFG RA459, SFB 518); the Danish Diabetes Association; the Danish Health Research Council; Diabetes UK; Doris Duke Charitable Foundation; Erasmus Medical Center (The Netherlands); the Dutch Diabetes Foundation; European Community (HEALTH-F4-2007-201413, HEALTH-2007-B-223211, LSHG-CT-2006-01947, LSHM-CT-2004-512013, LSHM-CT-2004-005272, LSHM-CT-2006-518153); the European Foundation for the Study of Diabetes; the Federal Ministry of Health (Germany); the Federal Ministry of Education and Research (Germany) (FKZ01GS0823 and DZD e.V.); F{\'e}d{\'e}ration Fran{\c c}aise de Cardiologie; The Finnish Diabetes Research Foundation; The Folkhalsan Research Foundation; The Foundation for Strategic Research (Sweden); The Foundation of Bristol-Myers Squibb; the German National Genome Research Network; Helmholtz Zentrum M{\"u}nchen-Research Center for Environment and Health; INSERM (France); La Fondation de France; Lilly; The Linnaeus Centre for Bioinformatics (Sweden); the Lundbeck Foundation Centre of Applied Medical Genomics for Personalized Disease Prediction, Prevention and Care; the Medical Research Council UK (G0601261, G0000649; 081696); Munich Center of Health Sciences-LMU Innovativ (Germany); Merck Sant{\'e}; the Ministry of Health and Department of Educational Assistance, University and Research of the Autonomous Province of Bolzano (Italy); the Ministry of Innovation, Science, Research and Technology of the State of North Rhine-Westphalia (Germany); the Ministry of Science, Education and Sport (Croatia); the National Heart, Lung, and Blood Institute (N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, N01-HC-25195, R01HL087641, R01HL59367, R01HL086694, N02-HL-6-4278); National Human Genome Research Institute (U01HG004402, U01HG004399, U01HG004171, 1 Z01 HG000024); the National Institute of Diabetes, Digestive and Kidney Diseases (DK078616, K24-DK080140, U54 DA021519, DK58845, DK069922, DK062370, DK073490, K23-DK65978 and DK072193); the US National Institutes of Health (HHSN268200625226C, HHSN268200625226C, 1K08AR055688, UL1RR025005, 1K99HL094535-01A1); the Netherlands Foundation for Scientific Research (175.010.2005.011, 047.017.043);",

year = "2010",

month = jul,

doi = "10.1038/ng.609",

language = "English (US)",

volume = "42",

pages = "579--589",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "7",

}

TY - JOUR

T1 - Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis

AU - Voight, Benjamin F.

AU - Scott, Laura J.

AU - Steinthorsdottir, Valgerdur

AU - Morris, Andrew P.

AU - Dina, Christian

AU - Welch, Ryan P.

AU - Zeggini, Eleftheria

AU - Huth, Cornelia

AU - Aulchenko, Yurii S.

AU - Thorleifsson, Gudmar

AU - McCulloch, Laura J.

AU - Ferreira, Teresa

AU - Grallert, Harald

AU - Amin, Najaf

AU - Wu, Guanming

AU - Willer, Cristen J.

AU - Raychaudhuri, Soumya

AU - McCarroll, Steve A.

AU - Langenberg, Claudia

AU - Hofmann, Oliver M.

AU - Dupuis, Josée

AU - Qi, Lu

AU - Segrè, Ayellet V.

AU - Van Hoek, Mandy

AU - Navarro, Pau

AU - Ardlie, Kristin

AU - Balkau, Beverley

AU - Benediktsson, Rafn

AU - Bennett, Amanda J.

AU - Blagieva, Roza

AU - Boerwinkle, Eric

AU - Bonnycastle, Lori L.

AU - Boström, Kristina Bengtsson

AU - Bravenboer, Bert

AU - Bumpstead, Suzannah

AU - Burtt, Noisël P.

AU - Charpentier, Guillaume

AU - Chines, Peter S.

AU - Cornelis, Marilyn

AU - Couper, David J.

AU - Crawford, Gabe

AU - Doney, Alex S F

AU - Elliott, Katherine S.

AU - Elliott, Amanda L.

AU - Erdos, Michael R.

AU - Fox, Caroline S.

AU - Franklin, Christopher S.

AU - Ganser, Martha

AU - Gieger, Christian

AU - Grarup, Niels

AU - Green, Todd

AU - Griffin, Simon

AU - Groves, Christopher J.

AU - Guiducci, Candace

AU - Hadjadj, Samy

AU - Hassanali, Neelam

AU - Herder, Christian

AU - Isomaa, Bo

AU - Jackson, Anne U.

AU - Johnson, Paul R V

AU - Jørgensen, Torben

AU - Kao, Wen H L

AU - Klopp, Norman

AU - Kong, Augustine

AU - Kraft, Peter

AU - Kuusisto, Johanna

AU - Lauritzen, Torsten

AU - Li, Man

AU - Lieverse, Aloysius

AU - Lindgren, Cecilia M.

AU - Lyssenko, Valeriya

AU - Marre, Michel

AU - Meitinger, Thomas

AU - Midthjell, Kristian

AU - Morken, Mario A.

AU - Narisu, Narisu

AU - Nilsson, Peter

AU - Owen, Katharine R.

AU - Payne, Felicity

AU - Perry, John R B

AU - Petersen, Ann Kristin

AU - Platou, Carl

AU - Proença, Christine

AU - Prokopenko, Inga

AU - Rathmann, Wolfgang

AU - Rayner, N. William

AU - Robertson, Neil R.

AU - Rocheleau, Ghislain

AU - Roden, Michael

AU - Sampson, Michael J.

AU - Saxena, Richa

AU - Shields, Beverley M.

AU - Shrader, Peter

AU - Sigurdsson, Gunnar

AU - Sparsø, Thomas

AU - Strassburger, Klaus

AU - Stringham, Heather M.

AU - Sun, Qi

AU - Swift, Amy J.

AU - Thorand, Barbara

AU - Tichet, Jean

AU - Tuomi, Tiinamaija

AU - Van Dam, Rob M.

AU - Van Haeften, Timon W.

AU - Van Herpt, Thijs

AU - Van Vliet-Ostaptchouk, Jana V.

AU - Walters, G. Bragi

AU - Weedon, Michael N.

AU - Wijmenga, Cisca

AU - Witteman, Jacqueline

AU - Bergman, Richard N.

AU - Cauchi, Stephane

AU - Collins, Francis S.

AU - Gloyn, Anna L.

AU - Gyllensten, Ulf

AU - Hansen, Torben

AU - Hide, Winston A.

AU - Hitman, Graham A.

AU - Hofman, Albert

AU - Hunter, David J.

AU - Hveem, Kristian

AU - Laakso, Markku

AU - Mohlke, Karen L.

AU - Morris, Andrew D.

AU - Palmer, Colin N A

AU - Pramstaller, Peter P.

AU - Rudan, Igor

AU - Sijbrands, Eric

AU - Stein, Lincoln D.

AU - Tuomilehto, Jaakko

AU - Uitterlinden, Andre

AU - Walker, Mark

AU - Wareham, Nicholas J.

AU - Watanabe, Richard M.

AU - Abecasis, Gonçalo R.

AU - Boehm, Bernhard O.

AU - Campbell, Harry

AU - Daly, Mark J.

AU - Hattersley, Andrew T.

AU - Hu, Frank B.

AU - Meigs, James B.

AU - Pankow, James S.

AU - Pedersen, Oluf

AU - Wichmann, H. Erich

AU - Barroso, Inês

AU - Florez, Jose C.

AU - Frayling, Timothy M.

AU - Groop, Leif

AU - Sladek, Rob

AU - Thorsteinsdottir, Unnur

AU - Wilson, James F.

AU - Illig, Thomas

AU - Froguel, Philippe

AU - Van Duijn, Cornelia M.

AU - Stefansson, Kari

AU - Altshuler, David

AU - Boehnke, Michael

AU - McCarthy, Mark I.

N1 - Funding Information: We acknowledge funding from: the Academy of Finland (no. 124243); Agence Nationale de la Recherche (France); American Diabetes Association (1-05-RA-140, 7-08-MN-OK; 7-06-MN-05); Ardix Medical; Association Diabète Risque Vasculaire; Association de Langue Française pour l’Etude du Diabète et des Maladies Métaboliques; Association Française des Diabétiques; Bayer Diagnostics; British Diabetic Association Research; Becton Dickinson; Broad Institute of Harvard and Massachusetts Institute of Technology; The Burroughs Wellcome Fund; Cardionics; Center for Inherited Disease Research (USA); Centre for Medical Systems Biology (The Netherlands); Centre of Excellence Metabolic Disorders Baden-Wuerttemberg (Germany); Caisse Nationale Assurance Maladie des Travailleurs Salariés (France); Clinical Research Institute HUCH Ltd; Deutsche Forschungsgemeinschaft (DFG GrK 1041, DFG RA459, SFB 518); the Danish Diabetes Association; the Danish Health Research Council; Diabetes UK; Doris Duke Charitable Foundation; Erasmus Medical Center (The Netherlands); the Dutch Diabetes Foundation; European Community (HEALTH-F4-2007-201413, HEALTH-2007-B-223211, LSHG-CT-2006-01947, LSHM-CT-2004-512013, LSHM-CT-2004-005272, LSHM-CT-2006-518153); the European Foundation for the Study of Diabetes; the Federal Ministry of Health (Germany); the Federal Ministry of Education and Research (Germany) (FKZ01GS0823 and DZD e.V.); Fédération Française de Cardiologie; The Finnish Diabetes Research Foundation; The Folkhalsan Research Foundation; The Foundation for Strategic Research (Sweden); The Foundation of Bristol-Myers Squibb; the German National Genome Research Network; Helmholtz Zentrum München-Research Center for Environment and Health; INSERM (France); La Fondation de France; Lilly; The Linnaeus Centre for Bioinformatics (Sweden); the Lundbeck Foundation Centre of Applied Medical Genomics for Personalized Disease Prediction, Prevention and Care; the Medical Research Council UK (G0601261, G0000649; 081696); Munich Center of Health Sciences-LMU Innovativ (Germany); Merck Santé; the Ministry of Health and Department of Educational Assistance, University and Research of the Autonomous Province of Bolzano (Italy); the Ministry of Innovation, Science, Research and Technology of the State of North Rhine-Westphalia (Germany); the Ministry of Science, Education and Sport (Croatia); the National Heart, Lung, and Blood Institute (N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, N01-HC-25195, R01HL087641, R01HL59367, R01HL086694, N02-HL-6-4278); National Human Genome Research Institute (U01HG004402, U01HG004399, U01HG004171, 1 Z01 HG000024); the National Institute of Diabetes, Digestive and Kidney Diseases (DK078616, K24-DK080140, U54 DA021519, DK58845, DK069922, DK062370, DK073490, K23-DK65978 and DK072193); the US National Institutes of Health (HHSN268200625226C, HHSN268200625226C, 1K08AR055688, UL1RR025005, 1K99HL094535-01A1); the Netherlands Foundation for Scientific Research (175.010.2005.011, 047.017.043);

PY - 2010/7

Y1 - 2010/7

N2 - By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P 5 × 10 8. These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits.

AB - By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P 5 × 10 8. These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits.

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U2 - 10.1038/ng.609

DO - 10.1038/ng.609

M3 - Article

C2 - 20581827

AN - SCOPUS:77954143522

SN - 1061-4036

VL - 42

SP - 579

EP - 589

JO - Nature Genetics

JF - Nature Genetics

IS - 7

ER -

Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis

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