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

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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 languageEnglish
Pages (from-to)77-81
Number of pages5
JournalNature Genetics
Issue number1
Publication statusPublished - Jan 2009

Bibliographical 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’ 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.


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