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

作者：Robert A. Scott, Vasiliki Lagou, Ryan 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, Cécile Lecœur, Dmitry Shungin, Serena Sanna, Carlo Sidore, P. Johnson, J. Wouter Jukema, Toby Johnson, Anubha Mahajan, Niek Verweij, Guðmar Þorleifsson, Jouke‐Jan Hottenga, Sonia H Shah, Albert V. Smith, Bengt Sennblad, Christian Gieger, Perttu P. Salo, Markus Perola, Nicholas John Timpson, David M. Evans, Beaté St Pourcain, Ying Wu, Jeanette S. Andrews, Jennie Hui, Lawrence F. Bielak, Wei Zhao, Momoko Horikoshi, Pau Navarro, Aaron J. Isaacs, Jeffrey R. O’Connell, Kathleen E. Stirrups, Véronique Vitart, Caroline Hayward, Tõnu Esko, Evelin Mihailov, Ross M. Fraser, Tove Fall, Benjamin Franklin Voight, Soumya Raychaudhuri, Han Chen, Cecilia M. Lindgren, Andrew Paul Morris, Nigel William Rayner, Neil Robertson, Denis Rybin, Ching‐Ti Liu, J. Beckmann, Sara M. Willems, Peter S. Chines, Anne Jackson, Hyun Min Kang, Heather M. Stringham, Kijoung S 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, Antonella Mulas, Ramaiah Nagaraja, Stella Trompet, Ian Ford, Stephan J. L. Bakker, Augustine Kong, Meena Kumari, Bruna Gigante, Christian Herder, Patricia B. Munroe, Mark J. Caulfield, Jula Antti, Massimo Mangino, Kerrin S. Small, Iva Miljkovic, Ching‐Ti Liu, Mustafa Atalay, Wieland Kieß, Alan L James, Fernando Rivadeneira, André Gerardus Uitterlinden, Colin N A Palmer, Alex S. F. Doney, Gonneke A. H. M. Willemsen, Johannes H. Smit, Susan Campbell, Ozren Polašek, Lori L. Bonnycastle, Serge Herçberg, Maria Dimitriou, Jennifer L. Bolton, Gerard R Fowkes, Peter Louis Kovacs, Jaana Lindström, Tatijana Zemunik, Stefania Bandinelli, Sarah H. Wild, Hanneke Basart, Wolfgang Rathmann, Harald Grallert, Winfried Maerz, Marcus Edi Kleber, Bernhard Otto Boehm, Annette Peters, Peter Paul Pramstaller, Michael A. Province, Ingrid B. Borecki, Nicholas D. Hastie, Igor Rudan, Harry Campbell, Hugh C Watkins, Martin Farrall, Michael Stümvoll, Luigi Ferrucci, Dawn M. Waterworth, Richard N. Bergman, Francis S. Collins, Jaakko Tuomilehto, Richard M. Watanabe, Eco J. C. de Geus, Brenda W.J.H. Penninx, Albert Hofman, Ben A. Oostra, Bruce M. Psaty, Péter Vollenweider, James Fox Wilson, Alan F Wright, G. Kees Hovingh, Andres Metspalu, Matti I.J. Uusitupa, Patrik K. E. Magnusson, Kirsten Ohm Kyvik, Jaakko A. 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 Richard Bornstein, Peter E. H. Schwarz, Timo Antero Lakka, Rainer Rauramaa, Linda S. Adair, George Davey Smith, Tim D Spector, Thomas Illig, Ulf dé Fairé, Anders Hamsten, Vilmundur G. Gudnason, Mika Kivimäki, Aroon Dinesh Hingorani, Sirkka M Keinanen-Kiukaanniemi, Timo Saaristo, Dorret Irene Boomsma, Kāri Stefánsson, Pim van der Harst, Josée Dupuis, Nancy L. Pedersen, Naveed Sattar, Tamara B. Harris, Francesco Cucca, Samuli Ripatti, Veikko V Salomaa, Karen L. Mohlke, Beverley Balkau, Philippe Froguel, Anneli Pouta, Marjo‐Riitta Järvelin, Nicholas J. Wareham, Nabila Bouatia‐Naji, Mark I. McCarthy, Paul W. Franks, James B. Meigs, Tanya M. Teslovich, José C. Florez, Claudia Langenberg, Erik Ingelsson, Inga Prokopenko, Inês Barroso · 发表于：Nature Genetics · 年份：2012 · DOI：10.1038/ng.2385 · 被引用次数：858 · 研究领域：Genetic Associations and Epidemiology、Genetic Mapping and Diversity in Plants and Animals、Lipid metabolism and biosynthesis

Jose Florez, Claudia Langenberg, Erik Ingelsson, Inga Prokopenko, Inês Barroso and colleagues perform large-scale association analyses using the Metabochip to gain further insights into the genetic architecture of glucose regulation. They identify 38 new loci influencing 1 or more glycemic traits and show that many of these loci also modify risk of type 2 diabetes. 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.