New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.[Erratum appears in Nat Genet.2010 May;42(5):464]: Nature Genetics

Josee 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 Magi, Andrew P. Morris, Joshua Randall, Toby Johnson, Paul Elliott, Denis Rybin, Gudmar Thorleifsson, Valgerdur Steinthorsdottir, Peter HennemanHarald Grallert, Abbas Dehghan, Jouke Jan Hottenga, Christopher S. Franklin, Pau Navarro, Kijoung Song, Anuj Goel, John R. B. Perry, Josephine M. Egan, Taina Lajunen, Niels Grarup, Thomas Sparso, Alex Doney, Benjamin F. Voight, Heather M. Stringham, Man Li, Stavroula Kanoni, Peter Shrader, Christine Cavalcanti-Proenca, 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, Francois 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, Amelie Bonnefond, Lori L. Bonnycastle, Knut Borch-Johnsen, Yvonne Bottcher, Eric Brunner, Suzannah J. Bumpstead, Guillaume Charpentier, Yii-Der Ida Chen, Peter Chines, Robert Clarke, Lachlan J. M. Coin, 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 Grazia Franzosi, Pilar Galan, Mark O. Goodarzi, Jurgen Graessler, Christopher J. Groves, Scott Grundy, Rhian Gwilliam, Ulf Gyllensten, et al. Hadjadj Samy

Research output: Contribution to journalArticle (Academic Journal)peer-review

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.

Bibliographical note

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Dupuis J Langenberg C Prokopenko I Saxena R Soranzo N Jackson AU Wheeler E Glazer NL Bouatia-Naji N Gloyn AL Lindgren CM Magi R Morris AP Randall J Johnson T Elliott P Rybin D Thorleifsson G Steinthorsdottir V Henneman P Grallert H Dehghan A Hottenga JJ Franklin CS Navarro P Song K Goel A Perry JR Egan JM Lajunen T Grarup N Sparso T Doney A Voight BF Stringham HM Li M Kanoni S Shrader P Cavalcanti-Proenca C Kumari M Qi L Timpson NJ Gieger C Zabena C Rocheleau G Ingelsson E An P O'Connell J Luan J Elliott A McCarroll SA Payne F Roccasecca RM Pattou F Sethupathy P Ardlie K Ariyurek Y Balkau B Barter P Beilby JP Ben-Shlomo Y Benediktsson R Bennett AJ Bergmann S Bochud M Boerwinkle E Bonnefond A Bonnycastle LL Borch-Johnsen K Bottcher Y Brunner E Bumpstead SJ Charpentier G Chen YD Chines P Clarke R Coin LJ Cooper MN Cornelis M Crawford G Crisponi L Day IN de Geus EJ Delplanque J Dina C Erdos MR Fedson AC Fischer-Rosinsky A Forouhi NG Fox CS Frants R Franzosi MG Galan P Goodarzi MO Graessler J Groves CJ Grundy S Gwilliam R Gyllensten U Hadjadj S Hallmans G Hammond N Han X Hartikainen AL Hassanali N Hayward C Heath SC Hercberg S Herder C Hicks AA Hillman DR Hingorani AD Hofman A Hui J Hung J Isomaa B Johnson PR Jorgensen T Jula A Kaakinen M Kaprio J Kesaniemi YA Kivimaki M Knight B Koskinen S Kovacs P Kyvik KO Lathrop GM Lawlor DA Le Bacquer O Lecoeur C Li Y Lyssenko V Mahley R Mangino M Manning AK Martinez-Larrad MT McAteer JB McCulloch LJ McPherson R Meisinger C Melzer D Meyre D Mitchell BD Morken MA Mukherjee S Naitza S Narisu N Neville MJ Oostra BA Orru M Pakyz R Palmer CN Paolisso G Pattaro C Pearson D Peden JF Pedersen NL Perola M Pfeiffer AF Pichler I Polasek O Posthuma D Potter SC Pouta A Province MA Psaty BM Rathmann W Rayner NW Rice K Ripatti S Rivadeneira F Roden M Rolandsson O Sandbaek A Sandhu M Sanna S Sayer AA Scheet P Scott LJ Seedorf U Sharp SJ Shields B Sigurethsson G Sijbrands EJ Silveira A Simpson L Singleton A Smith NL Sovio U Swift A Syddall H Syvanen AC Tanaka T Thorand B Tichet J Tonjes A Tuomi T Uitterlinden AG van Dijk KW van Hoek M Varma D Visvikis-Siest S Vitart V Vogelzangs N Waeber G Wagner PJ Walley A Walters GB Ward KL Watkins H Weedon MN Wild SH Willemsen G Witteman JC Yarnell JW Zeggini E Zelenika D Zethelius B Zhai G Zhao JH Zillikens MC DIAGRAM Consortium GIANT Consortium Global BPgen Consortium Borecki IB Loos RJ Meneton P Magnusson PK Nathan DM Williams GH Hattersley AT Silander K Salomaa V Smith GD Bornstein SR Schwarz P Spranger J Karpe F Shuldiner AR Cooper C Dedoussis GV Serrano-Rios M Morris AD Lind L Palmer LJ Hu FB Franks PW Ebrahim S Marmot M Kao WH Pankow JS Sampson MJ Kuusisto J Laakso M Hansen T Pedersen O Pramstaller PP Wichmann HE Illig T Rudan I Wright AF Stumvoll M Campbell H Wilson JF Anders Hamsten on behalf of Procardis Consortium MAGIC investigators Bergman RN Buchanan TA Collins FS Mohlke KL Tuomilehto J Valle TT Altshuler D Rotter JI Siscovick DS Penninx BW Boomsma DI Deloukas P Spector TD Frayling TM Ferrucci L Kong A Thorsteinsdottir U Stefansson K van Duijn CM Aulchenko YS Cao A Scuteri A Schlessinger D Uda M Ruokonen A Jarvelin MR Waterworth DM Vollenweider P Peltonen L Mooser V Abecasis GR Wareham NJ Sladek R Froguel P Watanabe RM Meigs JB Groop L Boehnke M McCarthy MI Florez JC Barroso I 077011 (United Kingdom Wellcome Trust) 077016 (United Kingdom Wellcome Trust) 081682 (United Kingdom Wellcome Trust) 088885 (United Kingdom Wellcome Trust) 089061 (United Kingdom Wellcome Trust) 091746 (United Kingdom Wellcome Trust) K24 DK080140-05 (United States NIDDK NIH HHS) P30 DK040561-14 (United States NIDDK NIH HHS) R01 DK078616-01A1 (United States NIDDK NIH HHS)

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