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 WJH 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

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 x 10(-50)) and reduced beta-cell function as measured by homeostasis model assessment (HOMA-B, P = 1.1 x 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 x 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 x 10(-57)) and GCK (rs4607517, P = 1.0 x 10(-25)) loci.