Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways by Scott Robert A, Lagou Vasiliki, Welch Ryan P, Wheeler Eleanor, Montasser May E, Luan Jian'an, Mägi Reedik, Strawbridge Rona J, Rehnberg Emil, Gustafsson Stefan, Kanoni Stavroula, Rasmussen-Torvik Laura J, Yengo Loïc, Lecoeur Cecile, Shungin Dmitry, Sanna Serena, Sidore Carlo, Johnson Paul C D, Jukema J Wouter, Johnson Toby, Mahajan Anubha, Verweij Niek, Thorleifsson Gudmar, Hottenga Jouke-Jan, Shah Sonia, Smith Albert V, Sennblad Bengt, Gieger Christian, Salo Perttu, Perola Markus, Timpson Nicholas J, Evans David M, Pourcain Beate St, Wu Ying, Andrews Jeanette S, Hui Jennie, Bielak Lawrence F, Zhao Wei, Horikoshi Momoko, Navarro Pau, Isaacs Aaron, O'Connell Jeffrey R, Stirrups Kathleen, Vitart Veronique, Hayward Caroline, Esko Tõnu, Mihailov Evelin, Fraser Ross M, Fall Tove, Voight Benjamin F, Raychaudhuri Soumya, Chen Han, Lindgren Cecilia M, Morris Andrew P, Rayner Nigel W, Robertson Neil, Rybin Denis, Liu Ching-Ti, Beckmann Jacques S, Willems Sara M, Chines Peter S, Jackson Anne U, Kang Hyun Min, Stringham Heather M, Song Kijoung, Tanaka Toshiko, Peden John F, Goel Anuj, Hicks Andrew A, An Ping, Müller-Nurasyid Martina, Franco-Cereceda Anders, Folkersen Lasse, Marullo Letizia, Jansen Hanneke, Oldehinkel Albertine J, Bruinenberg Marcel, Pankow James S, North Kari E, Forouhi Nita G, Loos Ruth J F, Edkins Sarah, Varga Tibor V, Hallmans Göran, Oksa Heikki, Antonella Mulas, Nagaraja Ramaiah, Trompet Stella, Ford Ian, Bakker Stephan J L, Kong Augustine, Kumari Meena, Gigante Bruna, Herder Christian, Munroe Patricia B, Caulfield Mark, Antti Jula, Mangino Massimo, Small Kerrin, Miljkovic Iva, Liu Yongmei, Atalay Mustafa, Kiess Wieland, James Alan L, Rivadeneira Fernando, Uitterlinden Andre G, Palmer Colin N A, Doney Alex S F, Willemsen Gonneke, Smit Johannes H, Campbell Susan, Polasek Ozren, Bonnycastle Lori L, Hercberg Serge, Dimitriou Maria, Bolton Jennifer L, Fowkes Gerard R, Kovacs Peter, Lindström Jaana, Zemunik Tatijana, Bandinelli Stefania, Wild Sarah H, Basart Hanneke V, Rathmann Wolfgang, Grallert Harald, DIAbetes Genetics Replication and Meta-analysis (DIAGRAM) Consortium, Maerz Winfried, Kleber Marcus E, Boehm Bernhard O, Peters Annette, Pramstaller Peter P, Province Michael A, Borecki Ingrid B, Hastie Nicholas D, Rudan Igor, Campbell Harry, Watkins Hugh, Farrall Martin, Stumvoll Michael, Ferrucci Luigi, Waterworth Dawn M, Bergman Richard N, Collins Francis S, Tuomilehto Jaakko, Watanabe Richard M, de Geus Eco J C, Penninx Brenda W, Hofman Albert, Oostra Ben A, Psaty Bruce M, Vollenweider Peter, Wilson James F, Wright Alan F, Hovingh G Kees, Metspalu Andres, Uusitupa Matti, Magnusson Patrik K E, Kyvik Kirsten O, Kaprio Jaakko, Price Jackie F, Dedoussis George V, Deloukas Panos, Meneton Pierre, Lind Lars, Boehnke Michael, Shuldiner Alan R, van Duijn Cornelia M, Morris Andrew D, Toenjes Anke, Peyser Patricia A, Beilby John P, Körner Antje, Kuusisto Johanna, Laakso Markku, Bornstein Stefan R, Schwarz Peter E H, Lakka Timo A, Rauramaa Rainer, Adair Linda S, Smith George Davey, Spector Tim D, Illig Thomas, de Faire Ulf, Hamsten Anders, Gudnason Vilmundur, Kivimaki Mika, Hingorani Aroon, Keinanen-Kiukaanniemi Sirkka M, Saaristo Timo E, Boomsma Dorret I, Stefansson Kari, van der Harst Pim, Dupuis Josée, Pedersen Nancy L, Sattar Naveed, Harris Tamara B, Cucca Francesco, Ripatti Samuli, Salomaa Veikko, Mohlke Karen L, Balkau Beverley, Froguel Philippe, Pouta Anneli, Jarvelin Marjo-Riitta, Wareham Nicholas J, Bouatia-Naji Nabila, McCarthy Mark I, Franks Paul W, Meigs James B, Teslovich Tanya M, Florez Jose C, Langenberg Claudia, Ingelsson Erik, Prokopenko Inga, Barroso Inês in Nature genetics (2012). PubMed

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.

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