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

Robert A. Scott, Vasiliki Lagou, Ryan P. Welch, Eleanor Wheeler, May E. Montasser, Jian'an Luan, Reedik MäGi, Rona J. Strawbridge, Emil Rehnberg, Sefan Gustafsson, Stavroula Kanoni, Laura J. Rasmussen-Torvik, Loic Yengo, Cecile Lecoeur, Dmitry Shungin, Serena Sanna, Carlo Sidore, Paul C.D. Johnson, J.Wouter Jukema, Toby JohnsonAnubha 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, Tonu 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 Muller-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, Goran Hallmans, Heikki Oksa, Antonella Mulas, Ramaiah Nagaraja, Stella Trompet, Ian Ford, 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, 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, Richard M Watanabe, 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, Jaakko Tuomilehto, Eco J C de Geus, Brenda W Penninx, Albert Hofman, Ben A Oostra, Bruce M Psaty, Peter Vollenweider, James F Wilson, G Kees Hovingh, Alan F Wright, 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 Korner, Johanna Kuusisto, Claudia Langenberg, Erik Ingelsson, 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, Pim van der Harst, Josee Dupuis, Stephan J. L. Bakker, Augustine Kong, Bruna Gigante, Meena Kumari, Christian Herder, Patricia B. Munroe, Mark Caulfield, Antti Jula, Massimo Mangino, Inga Prokopenko, Ines Barroso

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    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.
    Original languageEnglish
    Pages (from-to)991-1005
    Number of pages15
    JournalNature Genetics
    Volume44
    Issue number9
    DOIs
    Publication statusPublished - 2012

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  • Cite this

    Scott, R. A., Lagou, V., Welch, R. P., Wheeler, E., Montasser, M. E., Luan, J., MäGi, R., Strawbridge, R. J., Rehnberg, E., Gustafsson, S., Kanoni, S., Rasmussen-Torvik, L. J., Yengo, L., Lecoeur, C., Shungin, D., Sanna, S., Sidore, C., Johnson, P. C. D., Jukema, J. W., ... Barroso, I. (2012). Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways. Nature Genetics, 44(9), 991-1005. https://doi.org/10.1038/ng.2385