Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways.

Abstract

Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.

• Authors: Robert A Scott, Vasiliki Lagou, Ryan P Welch, Eleanor Wheeler, May E Montasser, Jian'an Luan, Reedik Mägi, Rona J Strawbridge, Emil Rehnberg, Stefan Gustafsson, Stavroula Kanoni, Laura J Rasmussen-Torvik, Loïc Yengo, Cecile Lecoeur, Dmitry Shungin, Serena Sanna, Carlo Sidore, Paul C D Johnson, J Wouter Jukema, Toby Johnson, Anubha Mahajan, Niek Verweij, Gudmar Thorleifsson, Jouke-Jan Hottenga, Sonia Shah, Albert V Smith, Bengt Sennblad, Christian Gieger, Perttu Salo, Markus Perola, Nicholas J Timpson, David M Evans, Beate St Pourcain, Ying Wu, Jeanette S Andrews, Jennie Hui, Lawrence F Bielak, Wei Zhao, Momoko Horikoshi, Pau Navarro, Aaron Isaacs, Jeffrey R O'Connell, Kathleen Stirrups, Veronique Vitart, Caroline Hayward, Tõnu Esko, Evelin Mihailov, Ross M Fraser, Tove Fall, Benjamin F Voight, Soumya Raychaudhuri, Han Chen, Cecilia M Lindgren, Andrew P Morris, Nigel W Rayner, Neil Robertson, Denis Rybin, Ching-Ti Liu, Jacques S Beckmann, Sara M Willems, Peter S Chines, Anne U Jackson, Hyun Min Kang, Heather M Stringham, Kijoung Song, Toshiko Tanaka, John F Peden, Anuj Goel, Andrew A Hicks, Ping An, Martina Müller-Nurasyid, Anders Franco-Cereceda, Lasse Folkersen, Letizia Marullo, Hanneke Jansen, Albertine J Oldehinkel, Marcel Bruinenberg, James S Pankow, Kari E North, Nita G Forouhi, Ruth J F Loos, Sarah Edkins, Tibor V Varga, Göran Hallmans, Heikki Oksa, Mulas Antonella, Ramaiah Nagaraja, Stella Trompet, Ian Ford, Stephan J L Bakker, Augustine Kong, Meena Kumari, Bruna Gigante, Christian Herder, Patricia B Munroe, Mark Caulfield, Jula Antti, Massimo Mangino, Kerrin Small, Iva Miljkovic, Yongmei Liu, Mustafa Atalay, Wieland Kiess, Alan L James, Fernando Rivadeneira, Andre G Uitterlinden, Colin N A Palmer, Alex S F Doney, Gonneke Willemsen, Johannes H Smit, Susan Campbell, Ozren Polasek, Lori L Bonnycastle, Serge Hercberg, Maria Dimitriou, Jennifer L Bolton, Gerard R Fowkes, Peter Kovacs, Jaana Lindström, Tatijana Zemunik, Stefania Bandinelli, Sarah H Wild, Hanneke V Basart, Wolfgang Rathmann, Harald Grallert, DIAbetes Genetics Replication and Meta-analysis (DIAGRAM) Consortium, Winfried Maerz, Marcus E Kleber, Bernhard O Boehm, Annette Peters, Peter P Pramstaller, Michael A Province, Ingrid B Borecki, Nicholas D Hastie, Igor Rudan, Harry Campbell, Hugh Watkins, Martin Farrall, Michael Stumvoll, Luigi Ferrucci, Dawn M Waterworth, Richard N Bergman, Francis S Collins, Jaakko Tuomilehto, Richard M Watanabe, Eco J C de Geus, Brenda W Penninx, Albert Hofman, Ben A Oostra, Bruce M Psaty, Peter Vollenweider, James F Wilson, Alan F Wright, G Kees Hovingh, Andres Metspalu, Matti Uusitupa, Patrik K E Magnusson, Kirsten O Kyvik, Jaakko Kaprio, Jackie F Price, George V Dedoussis, Panos Deloukas, Pierre Meneton, Lars Lind, Michael Boehnke, Alan R Shuldiner, Cornelia M van Duijn, Andrew D Morris, Anke Toenjes, Patricia A Peyser, John P Beilby, Antje Körner, Johanna Kuusisto, Markku Laakso, Stefan R Bornstein, Peter E H Schwarz, Timo A Lakka, Rainer Rauramaa, Linda S Adair, George Davey Smith, Tim D Spector, Thomas Illig, Ulf de Faire, Anders Hamsten, Vilmundur Gudnason, Mika Kivimaki, Aroon Hingorani, Sirkka M Keinanen-Kiukaanniemi, Timo E Saaristo, Dorret I Boomsma, Kari Stefansson, Pim van der Harst, Josée Dupuis, Nancy L Pedersen, Naveed Sattar, Tamara B Harris, Francesco Cucca, Samuli Ripatti, Veikko Salomaa, Karen L Mohlke, Beverley Balkau, Philippe Froguel, Anneli Pouta, Marjo-Riitta Jarvelin, Nicholas J Wareham, Nabila Bouatia-Naji, Mark I McCarthy, Paul W Franks, James B Meigs, Tanya M Teslovich, Jose C Florez, Claudia Langenberg, Erik Ingelsson, Inga Prokopenko, Inês Barroso
• Journal: Nature genetics (Nat Genet) Vol. 44 Issue 9 Pg. 991-1005 (Sep 2012) ISSN: 1546-1718 [Electronic] United States
• PMID: 22885924 (Publication Type: Journal Article, Meta-Analysis, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Blood Glucose
• Insulin

Topics

• Adult
• Animals
• Blood Glucose (genetics, metabolism)
• Fasting (blood, metabolism)
• Female
• Gene Frequency
• Genome-Wide Association Study (statistics & numerical data)
• Humans
• Insulin (blood)
• Male
• Metabolic Networks and Pathways (genetics)
• Mice
• Osmolar Concentration
• Quantitative Trait Loci (physiology)