Variants in MTNR1B influence fasting glucose levels

Inga Prokopenko; Claudia Langenberg; Jose C. Florez; Richa Saxena; Nicole Soranzo; Gudmar Thorleifsson; Ruth J.F. Loos; Alisa K. Manning; Anne U. Jackson; Yurii Aulchenko; Simon C. Potter; Michael R. Erdos; Serena Sanna; Jouke Jan Hottenga; Eleanor Wheeler; Marika Kaakinen; Valeriya Lyssenko; Wei Min Chen; Kourosh Ahmadi; Jacques S. Beckmann; Richard N. Bergman; Murielle Bochud; Lori L. Bonnycastle; Thomas A. Buchanan; Antonio Cao; Alessandra Cervino; Lachlan Coin; Francis S. Collins; Laura Crisponi; Eco J.C. De Geus; Abbas Dehghan; Panos Deloukas; Alex S.F. Doney; Paul Elliott; Nelson Freimer; Vesela Gateva; Christian Herder; Albert Hofman; Thomas E. Hughes; Sarah Hunt; Thomas Illig; Michael Inouye; Bo Isomaa; Toby Johnson; Augustine Kong; Maria Krestyaninova; Johanna Kuusisto; Markku Laakso; Noha Lim; Ulf Lindblad; Cecilia M. Lindgren; Owen T. McCann; Karen L. Mohlke; Andrew D. Morris; Silvia Naitza; Marco Orrù; Colin N.A. Palmer; Anneli Pouta; Joshua Randall; Wolfgang Rathmann; Jouko Saramies; Paul Scheet; Laura J. Scott; Angelo Scuteri; Stephen Sharp; Eric Sijbrands; Jan H. Smit; Kijoung Song; Valgerdur Steinthorsdottir; Heather M. Stringham; Tiinamaija Tuomi; Jaakko Tuomilehto; André G. Uitterlinden; Benjamin F. Voight; Dawn Waterworth; H. Erich Wichmann; Gonneke Willemsen; Jacqueline C.M. Witteman; Xin Yuan; Jing Hua Zhao; Eleftheria Zeggini; David Schlessinger; Manjinder Sandhu; Dorret I. Boomsma; Manuela Uda; Tim D. Spector; Brenda W.J.H. Penninx; David Altshuler; Peter Vollenweider; Marjo Riitta Jarvelin; Edward Lakatta; Gerard Waeber; Caroline S. Fox; Leena Peltonen; Leif C. Groop; Vincent Mooser; L. Adrienne Cupples; Unnur Thorsteinsdottir; Michael Boehnke; Inês Barroso; Cornelia Van Duijn; Josée Dupuis; Richard M. Watanabe; Kari Stefansson; Mark I. McCarthy; Nicholas J. Wareham; James B. Meigs; Gonçalo R. Abecasis

doi:10.1038/ng.290

Variants in MTNR1B influence fasting glucose levels

Inga Prokopenko, Claudia Langenberg, Jose C. Florez, Richa Saxena, Nicole Soranzo, Gudmar Thorleifsson, Ruth J.F. Loos, Alisa K. Manning, Anne U. Jackson, Yurii Aulchenko, Simon C. Potter, Michael R. Erdos, Serena Sanna, Jouke Jan Hottenga, Eleanor Wheeler, Marika Kaakinen, Valeriya Lyssenko, Wei Min Chen, Kourosh Ahmadi, Jacques S. BeckmannRichard N. Bergman, Murielle Bochud, Lori L. Bonnycastle, Thomas A. Buchanan, Antonio Cao, Alessandra Cervino, Lachlan Coin, Francis S. Collins, Laura Crisponi, Eco J.C. De Geus, Abbas Dehghan, Panos Deloukas, Alex S.F. Doney, Paul Elliott, Nelson Freimer, Vesela Gateva, Christian Herder, Albert Hofman, Thomas E. Hughes, Sarah Hunt, Thomas Illig, Michael Inouye, Bo Isomaa, Toby Johnson, Augustine Kong, Maria Krestyaninova, Johanna Kuusisto, Markku Laakso, Noha Lim, Ulf Lindblad, Cecilia M. Lindgren, Owen T. McCann, Karen L. Mohlke, Andrew D. Morris, Silvia Naitza, Marco Orrù, Colin N.A. Palmer, Anneli Pouta, Joshua Randall, Wolfgang Rathmann, Jouko Saramies, Paul Scheet, Laura J. Scott, Angelo Scuteri, Stephen Sharp, Eric Sijbrands, Jan H. Smit, Kijoung Song, Valgerdur Steinthorsdottir, Heather M. Stringham, Tiinamaija Tuomi, Jaakko Tuomilehto, André G. Uitterlinden, Benjamin F. Voight, Dawn Waterworth, H. Erich Wichmann, Gonneke Willemsen, Jacqueline C.M. Witteman, Xin Yuan, Jing Hua Zhao, Eleftheria Zeggini, David Schlessinger, Manjinder Sandhu, Dorret I. Boomsma, Manuela Uda, Tim D. Spector, Brenda W.J.H. Penninx, David Altshuler, Peter Vollenweider, Marjo Riitta Jarvelin, Edward Lakatta, Gerard Waeber, Caroline S. Fox, Leena Peltonen, Leif C. Groop, Vincent Mooser, L. Adrienne Cupples, Unnur Thorsteinsdottir, Michael Boehnke, Inês Barroso, Cornelia Van Duijn, Josée Dupuis, Richard M. Watanabe, Kari Stefansson, Mark I. McCarthy, Nicholas J. Wareham, James B. Meigs, Gonçalo R. Abecasis

School of Medicine

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

Abstract

To identify previously unknown genetic loci associated with fasting glucose concentrations, we examined the leading association signals in ten genome-wide association scans involving a total of 36,610 individuals of European descent. Variants in the gene encoding melatonin receptor 1B (MTNR1B) were consistently associated with fasting glucose across all ten studies. The strongest signal was observed at rs10830963, where each G allele (frequency 0.30 in HapMap CEU) was associated with an increase of 0.07 (95% CI = 0.06-0.08) mmol/l in fasting glucose levels (P = 3.2 × 10^-50) and reduced beta-cell function as measured by homeostasis model assessment (HOMA-B, P = 1.1 × 10 ^-15). The same allele was associated with an increased risk of type 2 diabetes (odds ratio = 1.09 (1.05-1.12), per G allele P = 3.3 × 10 ^-7) in a meta-analysis of 13 case-control studies totaling 18,236 cases and 64,453 controls. Our analyses also confirm previous associations of fasting glucose with variants at the G6PC2 (rs560887, P = 1.1 × 10 ^-57) and GCK (rs4607517, P = 1.0 × 10^-25) loci.

Original language	English (US)
Pages (from-to)	77-81
Number of pages	5
Journal	Nature genetics
Volume	41
Issue number	1
DOIs	https://doi.org/10.1038/ng.290
State	Published - Jan 2009

ASJC Scopus subject areas

Genetics

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10.1038/ng.290

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Prokopenko, I., Langenberg, C., Florez, J. C., Saxena, R., Soranzo, N., Thorleifsson, G., Loos, R. J. F., Manning, A. K., Jackson, A. U., Aulchenko, Y., Potter, S. C., Erdos, M. R., Sanna, S., Hottenga, J. J., Wheeler, E., Kaakinen, M., Lyssenko, V., Chen, W. M., Ahmadi, K., ... Abecasis, G. R. (2009). Variants in MTNR1B influence fasting glucose levels. Nature genetics, 41(1), 77-81. https://doi.org/10.1038/ng.290

Variants in MTNR1B influence fasting glucose levels. / Prokopenko, Inga; Langenberg, Claudia; Florez, Jose C.; Saxena, Richa; Soranzo, Nicole; Thorleifsson, Gudmar; Loos, Ruth J.F.; Manning, Alisa K.; Jackson, Anne U.; Aulchenko, Yurii; Potter, Simon C.; Erdos, Michael R.; Sanna, Serena; Hottenga, Jouke Jan; Wheeler, Eleanor; Kaakinen, Marika; Lyssenko, Valeriya; Chen, Wei Min; Ahmadi, Kourosh; Beckmann, Jacques S.; Bergman, Richard N.; Bochud, Murielle; Bonnycastle, Lori L.; Buchanan, Thomas A.; Cao, Antonio; Cervino, Alessandra; Coin, Lachlan; Collins, Francis S.; Crisponi, Laura; De Geus, Eco J.C.; Dehghan, Abbas; Deloukas, Panos; Doney, Alex S.F.; Elliott, Paul; Freimer, Nelson; Gateva, Vesela; Herder, Christian; Hofman, Albert; Hughes, Thomas E.; Hunt, Sarah; Illig, Thomas; Inouye, Michael; Isomaa, Bo; Johnson, Toby; Kong, Augustine; Krestyaninova, Maria; Kuusisto, Johanna; Laakso, Markku; Lim, Noha; Lindblad, Ulf; Lindgren, Cecilia M.; McCann, Owen T.; Mohlke, Karen L.; Morris, Andrew D.; Naitza, Silvia; Orrù, Marco; Palmer, Colin N.A.; Pouta, Anneli; Randall, Joshua; Rathmann, Wolfgang; Saramies, Jouko; Scheet, Paul; Scott, Laura J.; Scuteri, Angelo; Sharp, Stephen; Sijbrands, Eric; Smit, Jan H.; Song, Kijoung; Steinthorsdottir, Valgerdur; Stringham, Heather M.; Tuomi, Tiinamaija; Tuomilehto, Jaakko; Uitterlinden, André G.; Voight, Benjamin F.; Waterworth, Dawn; Wichmann, H. Erich; Willemsen, Gonneke; Witteman, Jacqueline C.M.; Yuan, Xin; Zhao, Jing Hua; Zeggini, Eleftheria; Schlessinger, David; Sandhu, Manjinder; Boomsma, Dorret I.; Uda, Manuela; Spector, Tim D.; Penninx, Brenda W.J.H.; Altshuler, David; Vollenweider, Peter; Jarvelin, Marjo Riitta; Lakatta, Edward; Waeber, Gerard; Fox, Caroline S.; Peltonen, Leena; Groop, Leif C.; Mooser, Vincent; Cupples, L. Adrienne; Thorsteinsdottir, Unnur; Boehnke, Michael; Barroso, Inês; Van Duijn, Cornelia; Dupuis, Josée; Watanabe, Richard M.; Stefansson, Kari; McCarthy, Mark I.; Wareham, Nicholas J.; Meigs, James B.; Abecasis, Gonçalo R.

In: Nature genetics, Vol. 41, No. 1, 01.2009, p. 77-81.

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

Prokopenko, I, Langenberg, C, Florez, JC, Saxena, R, Soranzo, N, Thorleifsson, G, Loos, RJF, Manning, AK, Jackson, AU, Aulchenko, Y, Potter, SC, Erdos, MR, Sanna, S, Hottenga, JJ, Wheeler, E, Kaakinen, M, Lyssenko, V, Chen, WM, Ahmadi, K, Beckmann, JS, Bergman, RN, Bochud, M, Bonnycastle, LL, Buchanan, TA, Cao, A, Cervino, A, Coin, L, Collins, FS, Crisponi, L, De Geus, EJC, Dehghan, A, Deloukas, P, Doney, ASF, Elliott, P, Freimer, N, Gateva, V, Herder, C, Hofman, A, Hughes, TE, Hunt, S, Illig, T, Inouye, M, Isomaa, B, Johnson, T, Kong, A, Krestyaninova, M, Kuusisto, J, Laakso, M, Lim, N, Lindblad, U, Lindgren, CM, McCann, OT, Mohlke, KL, Morris, AD, Naitza, S, Orrù, M, Palmer, CNA, Pouta, A, Randall, J, Rathmann, W, Saramies, J, Scheet, P, Scott, LJ, Scuteri, A, Sharp, S, Sijbrands, E, Smit, JH, Song, K, Steinthorsdottir, V, Stringham, HM, Tuomi, T, Tuomilehto, J, Uitterlinden, AG, Voight, BF, Waterworth, D, Wichmann, HE, Willemsen, G, Witteman, JCM, Yuan, X, Zhao, JH, Zeggini, E, Schlessinger, D, Sandhu, M, Boomsma, DI, Uda, M, Spector, TD, Penninx, BWJH, Altshuler, D, Vollenweider, P, Jarvelin, MR, Lakatta, E, Waeber, G, Fox, CS, Peltonen, L, Groop, LC, Mooser, V, Cupples, LA, Thorsteinsdottir, U, Boehnke, M, Barroso, I, Van Duijn, C, Dupuis, J, Watanabe, RM, Stefansson, K, McCarthy, MI, Wareham, NJ, Meigs, JB & Abecasis, GR 2009, 'Variants in MTNR1B influence fasting glucose levels', Nature genetics, vol. 41, no. 1, pp. 77-81. https://doi.org/10.1038/ng.290

Prokopenko, Inga ; Langenberg, Claudia ; Florez, Jose C. ; Saxena, Richa ; Soranzo, Nicole ; Thorleifsson, Gudmar ; Loos, Ruth J.F. ; Manning, Alisa K. ; Jackson, Anne U. ; Aulchenko, Yurii ; Potter, Simon C. ; Erdos, Michael R. ; Sanna, Serena ; Hottenga, Jouke Jan ; Wheeler, Eleanor ; Kaakinen, Marika ; Lyssenko, Valeriya ; Chen, Wei Min ; Ahmadi, Kourosh ; Beckmann, Jacques S. ; Bergman, Richard N. ; Bochud, Murielle ; Bonnycastle, Lori L. ; Buchanan, Thomas A. ; Cao, Antonio ; Cervino, Alessandra ; Coin, Lachlan ; Collins, Francis S. ; Crisponi, Laura ; De Geus, Eco J.C. ; Dehghan, Abbas ; Deloukas, Panos ; Doney, Alex S.F. ; Elliott, Paul ; Freimer, Nelson ; Gateva, Vesela ; Herder, Christian ; Hofman, Albert ; Hughes, Thomas E. ; Hunt, Sarah ; Illig, Thomas ; Inouye, Michael ; Isomaa, Bo ; Johnson, Toby ; Kong, Augustine ; Krestyaninova, Maria ; Kuusisto, Johanna ; Laakso, Markku ; Lim, Noha ; Lindblad, Ulf ; Lindgren, Cecilia M. ; McCann, Owen T. ; Mohlke, Karen L. ; Morris, Andrew D. ; Naitza, Silvia ; Orrù, Marco ; Palmer, Colin N.A. ; Pouta, Anneli ; Randall, Joshua ; Rathmann, Wolfgang ; Saramies, Jouko ; Scheet, Paul ; Scott, Laura J. ; Scuteri, Angelo ; Sharp, Stephen ; Sijbrands, Eric ; Smit, Jan H. ; Song, Kijoung ; Steinthorsdottir, Valgerdur ; Stringham, Heather M. ; Tuomi, Tiinamaija ; Tuomilehto, Jaakko ; Uitterlinden, André G. ; Voight, Benjamin F. ; Waterworth, Dawn ; Wichmann, H. Erich ; Willemsen, Gonneke ; Witteman, Jacqueline C.M. ; Yuan, Xin ; Zhao, Jing Hua ; Zeggini, Eleftheria ; Schlessinger, David ; Sandhu, Manjinder ; Boomsma, Dorret I. ; Uda, Manuela ; Spector, Tim D. ; Penninx, Brenda W.J.H. ; Altshuler, David ; Vollenweider, Peter ; Jarvelin, Marjo Riitta ; Lakatta, Edward ; Waeber, Gerard ; Fox, Caroline S. ; Peltonen, Leena ; Groop, Leif C. ; Mooser, Vincent ; Cupples, L. Adrienne ; Thorsteinsdottir, Unnur ; Boehnke, Michael ; Barroso, Inês ; Van Duijn, Cornelia ; Dupuis, Josée ; Watanabe, Richard M. ; Stefansson, Kari ; McCarthy, Mark I. ; Wareham, Nicholas J. ; Meigs, James B. ; Abecasis, Gonçalo R. / Variants in MTNR1B influence fasting glucose levels. In: Nature genetics. 2009 ; Vol. 41, No. 1. pp. 77-81.

@article{efb51de0bf114b8c9c3c2c0b4a557958,

title = "Variants in MTNR1B influence fasting glucose levels",

abstract = "To identify previously unknown genetic loci associated with fasting glucose concentrations, we examined the leading association signals in ten genome-wide association scans involving a total of 36,610 individuals of European descent. Variants in the gene encoding melatonin receptor 1B (MTNR1B) were consistently associated with fasting glucose across all ten studies. The strongest signal was observed at rs10830963, where each G allele (frequency 0.30 in HapMap CEU) was associated with an increase of 0.07 (95% CI = 0.06-0.08) mmol/l in fasting glucose levels (P = 3.2 × 10-50) and reduced beta-cell function as measured by homeostasis model assessment (HOMA-B, P = 1.1 × 10 -15). The same allele was associated with an increased risk of type 2 diabetes (odds ratio = 1.09 (1.05-1.12), per G allele P = 3.3 × 10 -7) in a meta-analysis of 13 case-control studies totaling 18,236 cases and 64,453 controls. Our analyses also confirm previous associations of fasting glucose with variants at the G6PC2 (rs560887, P = 1.1 × 10 -57) and GCK (rs4607517, P = 1.0 × 10-25) loci.",

author = "Inga Prokopenko and Claudia Langenberg and Florez, {Jose C.} and Richa Saxena and Nicole Soranzo and Gudmar Thorleifsson and Loos, {Ruth J.F.} and Manning, {Alisa K.} and Jackson, {Anne U.} and Yurii Aulchenko and Potter, {Simon C.} and Erdos, {Michael R.} and Serena Sanna and Hottenga, {Jouke Jan} and Eleanor Wheeler and Marika Kaakinen and Valeriya Lyssenko and Chen, {Wei Min} and Kourosh Ahmadi and Beckmann, {Jacques S.} and Bergman, {Richard N.} and Murielle Bochud and Bonnycastle, {Lori L.} and Buchanan, {Thomas A.} and Antonio Cao and Alessandra Cervino and Lachlan Coin and Collins, {Francis S.} and Laura Crisponi and {De Geus}, {Eco J.C.} and Abbas Dehghan and Panos Deloukas and Doney, {Alex S.F.} and Paul Elliott and Nelson Freimer and Vesela Gateva and Christian Herder and Albert Hofman and Hughes, {Thomas E.} and Sarah Hunt and Thomas Illig and Michael Inouye and Bo Isomaa and Toby Johnson and Augustine Kong and Maria Krestyaninova and Johanna Kuusisto and Markku Laakso and Noha Lim and Ulf Lindblad and Lindgren, {Cecilia M.} and McCann, {Owen T.} and Mohlke, {Karen L.} and Morris, {Andrew D.} and Silvia Naitza and Marco Orr{\`u} and Palmer, {Colin N.A.} and Anneli Pouta and Joshua Randall and Wolfgang Rathmann and Jouko Saramies and Paul Scheet and Scott, {Laura J.} and Angelo Scuteri and Stephen Sharp and Eric Sijbrands and Smit, {Jan H.} and Kijoung Song and Valgerdur Steinthorsdottir and Stringham, {Heather M.} and Tiinamaija Tuomi and Jaakko Tuomilehto and Uitterlinden, {Andr{\'e} G.} and Voight, {Benjamin F.} and Dawn Waterworth and Wichmann, {H. Erich} and Gonneke Willemsen and Witteman, {Jacqueline C.M.} and Xin Yuan and Zhao, {Jing Hua} and Eleftheria Zeggini and David Schlessinger and Manjinder Sandhu and Boomsma, {Dorret I.} and Manuela Uda and Spector, {Tim D.} and Penninx, {Brenda W.J.H.} and David Altshuler and Peter Vollenweider and Jarvelin, {Marjo Riitta} and Edward Lakatta and Gerard Waeber and Fox, {Caroline S.} and Leena Peltonen and Groop, {Leif C.} and Vincent Mooser and Cupples, {L. Adrienne} and Unnur Thorsteinsdottir and Michael Boehnke and In{\^e}s Barroso and {Van Duijn}, Cornelia and Jos{\'e}e Dupuis and Watanabe, {Richard M.} and Kari Stefansson and McCarthy, {Mark I.} and Wareham, {Nicholas J.} and Meigs, {James B.} and Abecasis, {Gon{\c c}alo R.}",

note = "Funding Information: The authors would like to thank the many colleagues who contributed to collection and phenotypic characterization of the clinical samples, as well as genotyping and analysis of the GWA data. They would also like to acknowledge those who agreed to participate in these studies. Major funding for the work described in this paper comes from Academy of Finland (124243); the Administration of Lanusei, Ilbono, Arzana and Elini (Sardinia, Italy); American Diabetes Association (1-05-RA-140); the Center for Inherited Disease Research; Clinical Research Institute (HUCH); Diabetes UK; the European Bioinformatics Institute; the European Commission (contracts LSHM-CT-2006-037197, LSHM-CT-2003-503041, QLK6-CT-2002-02629, QLG2-CT-2002-01254, HEALTH-F4-2007-201413, LSHG-CT-2004-512066, QLRT-2001-01254, LSHG-CT-2004-518153); the Faculty of Biology and Medicine of Lausanne; Finnish Diabetes Research Foundation; Folkhalsan Research Foundation; Foundation of the NIH (GAIN initiative); German Federal Ministry of Education and Research; German Federal Ministry of Health and Social Security; German National Genome Research Network; GlaxoSmithKline; GSF-National Research Center for Environment and Health; LMUinnovativ; Ministry of Science and Research of the State North-Rhine Westphalia; Municipality of Rotterdam; US National Institutes of Health (HG-02651, HL-084729, HL-087679, HC-25195, N02-HL-6-4278, DK-078616, DK-080140, DK-065978, RR-163736, MH059160, DK069922, DA-021519, DK-062370, DK-072193, US National Human Genome Research Institute intramural project HG-000024; and the Intramural Program of the National Institute on Aging); the UK National Institute for Health Research (Oxford Biomedical Research Centre and Guys and St. Thomas{\textquoteright} Biomedical Research Centre); the Netherlands Ministry of Education, Culture and Science; the Netherlands Ministry of Health, Welfare and Sports; Novartis; NWO (904-61-090, 904-61-193, 480-04-004, 400-05-717); NWOGenomics; NWOInvestments; Research Institute for Diseases in the Elderly (RIDE); Sigrid Juselius Foundation; Spinozapremie; Swedish Research Council (349-2006-237); UK Medical Research Council (G0500539, G0000649, G016121); UK National Health Services Research and Development; the Wellcome Trust (including intramural support for the Wellcome Trust Sanger Institute, GR069224, Strategic Awards 076113 and 083948, Biomedical Collections Grant GR072960); and ZonMw (10-000-1002). A full list of acknowledgments is provided in the Supplementary Note.",

year = "2009",

month = jan,

doi = "10.1038/ng.290",

language = "English (US)",

volume = "41",

pages = "77--81",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - Variants in MTNR1B influence fasting glucose levels

AU - Prokopenko, Inga

AU - Langenberg, Claudia

AU - Florez, Jose C.

AU - Saxena, Richa

AU - Soranzo, Nicole

AU - Thorleifsson, Gudmar

AU - Loos, Ruth J.F.

AU - Manning, Alisa K.

AU - Jackson, Anne U.

AU - Aulchenko, Yurii

AU - Potter, Simon C.

AU - Erdos, Michael R.

AU - Sanna, Serena

AU - Hottenga, Jouke Jan

AU - Wheeler, Eleanor

AU - Kaakinen, Marika

AU - Lyssenko, Valeriya

AU - Chen, Wei Min

AU - Ahmadi, Kourosh

AU - Beckmann, Jacques S.

AU - Bergman, Richard N.

AU - Bochud, Murielle

AU - Bonnycastle, Lori L.

AU - Buchanan, Thomas A.

AU - Cao, Antonio

AU - Cervino, Alessandra

AU - Coin, Lachlan

AU - Collins, Francis S.

AU - Crisponi, Laura

AU - De Geus, Eco J.C.

AU - Dehghan, Abbas

AU - Deloukas, Panos

AU - Doney, Alex S.F.

AU - Elliott, Paul

AU - Freimer, Nelson

AU - Gateva, Vesela

AU - Herder, Christian

AU - Hofman, Albert

AU - Hughes, Thomas E.

AU - Hunt, Sarah

AU - Illig, Thomas

AU - Inouye, Michael

AU - Isomaa, Bo

AU - Johnson, Toby

AU - Kong, Augustine

AU - Krestyaninova, Maria

AU - Kuusisto, Johanna

AU - Laakso, Markku

AU - Lim, Noha

AU - Lindblad, Ulf

AU - Lindgren, Cecilia M.

AU - McCann, Owen T.

AU - Mohlke, Karen L.

AU - Morris, Andrew D.

AU - Naitza, Silvia

AU - Orrù, Marco

AU - Palmer, Colin N.A.

AU - Pouta, Anneli

AU - Randall, Joshua

AU - Rathmann, Wolfgang

AU - Saramies, Jouko

AU - Scheet, Paul

AU - Scott, Laura J.

AU - Scuteri, Angelo

AU - Sharp, Stephen

AU - Sijbrands, Eric

AU - Smit, Jan H.

AU - Song, Kijoung

AU - Steinthorsdottir, Valgerdur

AU - Stringham, Heather M.

AU - Tuomi, Tiinamaija

AU - Tuomilehto, Jaakko

AU - Uitterlinden, André G.

AU - Voight, Benjamin F.

AU - Waterworth, Dawn

AU - Wichmann, H. Erich

AU - Willemsen, Gonneke

AU - Witteman, Jacqueline C.M.

AU - Yuan, Xin

AU - Zhao, Jing Hua

AU - Zeggini, Eleftheria

AU - Schlessinger, David

AU - Sandhu, Manjinder

AU - Boomsma, Dorret I.

AU - Uda, Manuela

AU - Spector, Tim D.

AU - Penninx, Brenda W.J.H.

AU - Altshuler, David

AU - Vollenweider, Peter

AU - Jarvelin, Marjo Riitta

AU - Lakatta, Edward

AU - Waeber, Gerard

AU - Fox, Caroline S.

AU - Peltonen, Leena

AU - Groop, Leif C.

AU - Mooser, Vincent

AU - Cupples, L. Adrienne

AU - Thorsteinsdottir, Unnur

AU - Boehnke, Michael

AU - Barroso, Inês

AU - Van Duijn, Cornelia

AU - Dupuis, Josée

AU - Watanabe, Richard M.

AU - Stefansson, Kari

AU - McCarthy, Mark I.

AU - Wareham, Nicholas J.

AU - Meigs, James B.

AU - Abecasis, Gonçalo R.

N1 - Funding Information: The authors would like to thank the many colleagues who contributed to collection and phenotypic characterization of the clinical samples, as well as genotyping and analysis of the GWA data. They would also like to acknowledge those who agreed to participate in these studies. Major funding for the work described in this paper comes from Academy of Finland (124243); the Administration of Lanusei, Ilbono, Arzana and Elini (Sardinia, Italy); American Diabetes Association (1-05-RA-140); the Center for Inherited Disease Research; Clinical Research Institute (HUCH); Diabetes UK; the European Bioinformatics Institute; the European Commission (contracts LSHM-CT-2006-037197, LSHM-CT-2003-503041, QLK6-CT-2002-02629, QLG2-CT-2002-01254, HEALTH-F4-2007-201413, LSHG-CT-2004-512066, QLRT-2001-01254, LSHG-CT-2004-518153); the Faculty of Biology and Medicine of Lausanne; Finnish Diabetes Research Foundation; Folkhalsan Research Foundation; Foundation of the NIH (GAIN initiative); German Federal Ministry of Education and Research; German Federal Ministry of Health and Social Security; German National Genome Research Network; GlaxoSmithKline; GSF-National Research Center for Environment and Health; LMUinnovativ; Ministry of Science and Research of the State North-Rhine Westphalia; Municipality of Rotterdam; US National Institutes of Health (HG-02651, HL-084729, HL-087679, HC-25195, N02-HL-6-4278, DK-078616, DK-080140, DK-065978, RR-163736, MH059160, DK069922, DA-021519, DK-062370, DK-072193, US National Human Genome Research Institute intramural project HG-000024; and the Intramural Program of the National Institute on Aging); the UK National Institute for Health Research (Oxford Biomedical Research Centre and Guys and St. Thomas’ Biomedical Research Centre); the Netherlands Ministry of Education, Culture and Science; the Netherlands Ministry of Health, Welfare and Sports; Novartis; NWO (904-61-090, 904-61-193, 480-04-004, 400-05-717); NWOGenomics; NWOInvestments; Research Institute for Diseases in the Elderly (RIDE); Sigrid Juselius Foundation; Spinozapremie; Swedish Research Council (349-2006-237); UK Medical Research Council (G0500539, G0000649, G016121); UK National Health Services Research and Development; the Wellcome Trust (including intramural support for the Wellcome Trust Sanger Institute, GR069224, Strategic Awards 076113 and 083948, Biomedical Collections Grant GR072960); and ZonMw (10-000-1002). A full list of acknowledgments is provided in the Supplementary Note.

PY - 2009/1

Y1 - 2009/1

N2 - To identify previously unknown genetic loci associated with fasting glucose concentrations, we examined the leading association signals in ten genome-wide association scans involving a total of 36,610 individuals of European descent. Variants in the gene encoding melatonin receptor 1B (MTNR1B) were consistently associated with fasting glucose across all ten studies. The strongest signal was observed at rs10830963, where each G allele (frequency 0.30 in HapMap CEU) was associated with an increase of 0.07 (95% CI = 0.06-0.08) mmol/l in fasting glucose levels (P = 3.2 × 10-50) and reduced beta-cell function as measured by homeostasis model assessment (HOMA-B, P = 1.1 × 10 -15). The same allele was associated with an increased risk of type 2 diabetes (odds ratio = 1.09 (1.05-1.12), per G allele P = 3.3 × 10 -7) in a meta-analysis of 13 case-control studies totaling 18,236 cases and 64,453 controls. Our analyses also confirm previous associations of fasting glucose with variants at the G6PC2 (rs560887, P = 1.1 × 10 -57) and GCK (rs4607517, P = 1.0 × 10-25) loci.

AB - To identify previously unknown genetic loci associated with fasting glucose concentrations, we examined the leading association signals in ten genome-wide association scans involving a total of 36,610 individuals of European descent. Variants in the gene encoding melatonin receptor 1B (MTNR1B) were consistently associated with fasting glucose across all ten studies. The strongest signal was observed at rs10830963, where each G allele (frequency 0.30 in HapMap CEU) was associated with an increase of 0.07 (95% CI = 0.06-0.08) mmol/l in fasting glucose levels (P = 3.2 × 10-50) and reduced beta-cell function as measured by homeostasis model assessment (HOMA-B, P = 1.1 × 10 -15). The same allele was associated with an increased risk of type 2 diabetes (odds ratio = 1.09 (1.05-1.12), per G allele P = 3.3 × 10 -7) in a meta-analysis of 13 case-control studies totaling 18,236 cases and 64,453 controls. Our analyses also confirm previous associations of fasting glucose with variants at the G6PC2 (rs560887, P = 1.1 × 10 -57) and GCK (rs4607517, P = 1.0 × 10-25) loci.

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U2 - 10.1038/ng.290

DO - 10.1038/ng.290

M3 - Article

C2 - 19060907

AN - SCOPUS:58149156287

VL - 41

SP - 77

EP - 81

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 1

ER -