New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

Josée Dupuis, Claudia Langenberg, Inga Prokopenko, Richa Saxena, Nicole Soranzo, Anne U. Jackson, Eleanor Wheeler, Nicole L. Glazer, Nabila Bouatia-Naji, Anna L. Gloyn, Cecilia M. Lindgren, Reedik Mägi, Andrew P. Morris, Joshua Randall, Toby Johnson, Paul Elliott, Denis Rybin, Gudmar Thorleifsson, Valgerdur Steinthorsdottir, Peter HennemanHarald Grallert, Abbas Dehghan, Jouke JanHottenga, Christopher S. Franklin, Pau Navarro, Kijoung Song, Anuj Goel, John R B Perry, Josephine M. Egan, Taina Lajunen, Niels Grarup, Thomas Sparsø, Alex Doney, Benjamin F. Voight, Heather M. Stringham, Man Li, Stavroula Kanoni, Peter Shrader, Christine Cavalcanti-Proença, Meena Kumari, Lu Qi, Nicholas J. Timpson, Christian Gieger, Carina Zabena, Ghislain Rocheleau, Erik Ingelsson, Ping An, Jeffrey O'Connell, Jian'An Luan, Amanda Elliott, Steven A. McCarroll, Felicity Payne, Rosa Maria Roccasecca, François Pattou, Praveen Sethupathy, Kristin Ardlie, Yavuz Ariyurek, Beverley Balkau, Philip Barter, John P. Beilby, Yoav Ben-Shlomo, Rafn Benediktsson, Amanda J. Bennett, Sven Bergmann, Murielle Bochud, Eric Boerwinkle, Amélie Bonnefond, Lori L. Bonnycastle, Knut Borch-Johnsen, Yvonne Böttcher, Eric Brunner, Suzannah J. Bumpstead, Guillaume Charpentier, Yii Der IdaChen, Peter Chines, Robert Clarke, Lachlan J. McOin, Matthew N. Cooper, Marilyn Cornelis, Gabe Crawford, Laura Crisponi, Ian N M Day, Eco J C De Geus, Jerome Delplanque, Christian Dina, Michael R. Erdos, Annette C. Fedson, Antje Fischer-Rosinsky, Nita G. Forouhi, Caroline S. Fox, Rune Frants, Maria GraziaFranzosi, Pilar Galan, Mark O. Goodarzi, Jürgen Graessler, Christopher J. Groves, Scott Grundy, Rhian Gwilliam, Ulf Gyllensten, Samy Hadjadj, Göran Hallmans, Naomi Hammond, Xijing Han, Anna -LiisaHartikainen, Neelam Hassanali, Caroline Hayward, Simon C. Heath, Serge Hercberg, Christian Herder, Andrew A. Hicks, David R. Hillman, Aroon D. Hingorani, Albert Hofman, Jennie Hui, Joe Hung, Bo Isomaa, Paul R V Johnson, Torben Jørgensen, Antti Jula, Marika Kaakinen, Jaakko Kaprio, Y. AnteroKesaniemi, Mika Kivimaki, Beatrice Knight, Seppo Koskinen, Peter Kovacs, Kirsten Ohm Kyvik, G. Mark Lathrop, Debbie A. Lawlor, Olivier Le Bacquer, Cécile Lecoeur, Yun Li, Valeriya Lyssenko, Robert Mahley, Massimo Mangino, Alisa K. Manning, María TeresaMartínez-Larrad, Jarred B. McAteer, Laura J. McCulloch, Ruth McPherson, Christa Meisinger, David Melzer, David Meyre, Braxton D. Mitchell, Mario A. Morken, Sutapa Mukherjee, Silvia Naitza, Narisu Narisu, Matthew J. Neville, Ben A. Oostra, Marco Orrù, Ruth Pakyz, Colin N. APalmer, Giuseppe Paolisso, Cristian Pattaro, Daniel Pearson, John F. Peden, Nancy L. Pedersen, Markus Perola, Andreas F H Pfeiffer, Irene Pichler, Ozren Polasek, Danielle Posthuma, Simon C. Potter, Anneli Pouta, Michael A. Province, Bruce M. Psaty, Wolfgang Rathmann, Nigel W. Rayner, Kenneth Rice, Samuli Ripatti, Fernando Rivadeneira, Michael Roden, Olov Rolandsson, Annelli Sandbaek, Manjinder Sandhu, Serena Sanna, Avan Aihie Sayer, Paul Scheet, Laura J. Scott, Udo Seedorf, Stephen J. Sharp, Beverley Shields, Gunnar Sigursson, Eric J G Sijbrands, Angela Silveira, Laila Simpson, Andrew Singleton, Nicholas L. Smith, Ulla Sovio, Amy Swift, Holly Syddall, Ann -ChristineSyvänen, Toshiko Tanaka, Barbara Thorand, Jean Tichet, Anke Tönjes, Tiinamaija Tuomi, André G. Uitterlinden, Ko Willems Van Dijk, Mandy Van Hoek, Dhiraj Varma, Sophie Visvikis-Siest, Veronique Vitart, Nicole Vogelzangs, Gérard Waeber, Peter J. Wagner, Andrew Walley, G. BragiWalters, Kim L. Ward, Hugh Watkins, Michael N. Weedon, Sarah H. Wild, Gonneke Willemsen, Jaqueline C. MWitteman, John W. GYarnell, Eleftheria Zeggini, Diana Zelenika, Björn Zethelius, Guangju Zhai, Jing Hua Zhao, M. Carola Zillikens, Ingrid B. Borecki, Ruth J F Loos, Pierre Meneton, Patrik K E Magnusson, David M. Nathan, Gordon H. Williams, Andrew T. Hattersley, Kaisa Silander, Veikko Salomaa, George Davey Smith, Stefan R. Bornstein, Peter Schwarz, Joachim Spranger, Fredrik Karpe, Alan R. Shuldiner, Cyrus Cooper, George V. Dedoussis, Manuel Serrano-Ríos, Andrew D. Morris, Lars Lind, Lyle J. Palmer, Frank B. Hu, Paul W. Franks, Shah Ebrahim, Michael Marmot, W. H. Linda Kao, James S. Pankow, Michael J. Sampson, Johanna Kuusisto, Markku Laakso, Torben Hansen, Oluf Pedersen, Peter Paul Pramstaller, H. Erich Wichmann, Thomas Illig, Igor Rudan, Alan F. Wright, Michael Stumvoll, Harry Campbell, James F. Wilson, Richard N. Bergman, Thomas A. Buchanan, Francis S. Collins, Karen L. Mohlke, Jaakko Tuomilehto, Timo T. Valle, David Altshuler, Jerome I. Rotter, David S. Siscovick, Brenda W J H Penninx, Dorret I. Boomsma, Panos Deloukas, Timothy D. Spector, Timothy M. Frayling, Luigi Ferrucci, Augustine Kong, Unnur Thorsteinsdottir, Kari Stefansson, Cornelia M. Van Duijn, Yurii S. Aulchenko, Antonio Cao, Angelo Scuteri, David Schlessinger, Manuela Uda, Aimo Ruokonen, Marjo -RiittaJarvelin, Dawn M. Waterworth, Peter Vollenweider, Leena Peltonen, Vincent Mooser, Goncalo R. Abecasis, Nicholas J. Wareham, Robert Sladek, Philippe Froguel, Richard M. Watanabe, James B. Meigs, Leif Groop, Michael Boehnke, Mark I. McCarthy, Jose C. Florez, Inês Barroso

Research output: Contribution to journalArticle

Abstract

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

Original languageEnglish
Pages (from-to)105-116
Number of pages12
JournalNature Genetics
Volume42
Issue number2
DOIs
Publication statusPublished - Feb 2010

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ASJC Scopus subject areas

  • Genetics

Cite this

Dupuis, J., Langenberg, C., Prokopenko, I., Saxena, R., Soranzo, N., Jackson, A. U., Wheeler, E., Glazer, N. L., Bouatia-Naji, N., Gloyn, A. L., Lindgren, C. M., Mägi, R., Morris, A. P., Randall, J., Johnson, T., Elliott, P., Rybin, D., Thorleifsson, G., Steinthorsdottir, V., ... Barroso, I. (2010). New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nature Genetics, 42(2), 105-116. https://doi.org/10.1038/ng.520