A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance

Alisa K. Manning, Marie France Hivert, Robert A. Scott, Jonna L. Grimsby, Nabila Bouatia-Naji, Han Chen, Denis Rybin, Ching Ti Liu, Lawrence F. Bielak, Inga Prokopenko, Najaf Amin, Daniel Barnes, Gemma Cadby, Jouke Jan Hottenga, Erik Ingelsson, Anne U. Jackson, Toby Johnson, Stavroula Kanoni, Claes Ladenvall, Vasiliki LagouJari Lahti, Cecile Lecoeur, Yongmei Liu, Maria Teresa Martinez-Larrad, May E. Montasser, Pau Navarro, John R.B. Perry, Laura J. Rasmussen-Torvik, Perttu Salo, Naveed Sattar, Dmitry Shungin, Rona J. Strawbridge, Toshiko Tanaka, Cornelia M. Van Duijn, Ping An, Mariza De Andrade, Jeanette S. Andrews, Thor Aspelund, Mustafa Atalay, Yurii Aulchenko, Beverley Balkau, Stefania Bandinelli, Jacques S. Beckmann, John P. Beilby, Claire Bellis, Richard N. Bergman, John Blangero, Mladen Boban, Michael Boehnke, Eric Boerwinkle, Lori L. Bonnycastle, Dorret I. Boomsma, Ingrid B. Borecki, Yvonne Böttcher, Claude Bouchard, Eric Brunner, Danijela Budimir, Harry Campbell, Olga Carlson, Peter S. Chines, Robert Clarke, Francis S. Collins, Arturo Corbató-Anchuelo, David Couper, Ulf De Faire, George V. Dedoussis, Panos Deloukas, Maria Dimitriou, Josephine M. Egan, Gudny Eiriksdottir, Michael R. Erdos, Johan G. Eriksson, Elodie Eury, Luigi Ferrucci, Ian Ford, Nita G. Forouhi, Caroline S. Fox, Maria Grazia Franzosi, Paul W. Franks, Timothy M. Frayling, Philippe Froguel, Pilar Galan, Eco De Geus, Bruna Gigante, Nicole L. Glazer, Anuj Goel, Leif Groop, Vilmundur Gudnason, Göran Hallmans, Anders Hamsten, Ola Hansson, Tamara B. Harris, Caroline Hayward, Simon Heath, Serge Hercberg, Andrew A. Hicks, Aroon Hingorani, Albert Hofman, Jennie Hui, Joseph Hung, Marjo Riitta Jarvelin, Min A. Jhun, Paul C.D. Johnson, J. Wouter Jukema, Antti Jula, W. H. Kao, Jaakko Kaprio, Sharon L.R. Kardia, Sirkka Keinanen-Kiukaanniemi, Mika Kivimaki, Ivana Kolcic, Peter Kovacs, Meena Kumari, Johanna Kuusisto, Kirsten Ohm Kyvik, Markku Laakso, Timo Lakka, Lars Lannfelt, G. Mark Lathrop, Lenore J. Launer, Karin Leander, Guo Li, Lars Lind, Jaana Lindstrom, Stéphane Lobbens, Ruth J.F. Loos, Jian'An Luan, Valeriya Lyssenko, Reedik Mägi, Patrik K.E. Magnusson, Michael Marmot, Pierre Meneton, Karen L. Mohlke, Vincent Mooser, Mario A. Morken, Iva Miljkovic, Narisu Narisu, Jeff O'Connell, Ken K. Ong, Ben A. Oostra, Lyle J. Palmer, Aarno Palotie, James S. Pankow, John F. Peden, Nancy L. Pedersen, Marina Pehlic, Leena Peltonen, Brenda Penninx, Marijana Pericic, Markus Perola, Louis Perusse, Patricia A. Peyser, Ozren Polasek, Peter P. Pramstaller, Michael A. Province, Katri Räikkönen, Rainer Rauramaa, Emil Rehnberg, Ken Rice, Jerome I. Rotter, Igor Rudan, Aimo Ruokonen, Timo Saaristo, Maria Sabater-Lleal, Veikko Salomaa, David B. Savage, Richa Saxena, Peter Schwarz, Udo Seedorf, Bengt Sennblad, Manuel Serrano-Rios, Alan R. Shuldiner, Eric J.G. Sijbrands, David S. Siscovick, Johannes H. Smit, Kerrin S. Small, Nicholas L. Smith, Albert Vernon Smith, Alena Stančáková, Kathleen Stirrups, Michael Stumvoll, Yan V. Sun, Amy J. Swift, Anke Tönjes, Jaakko Tuomilehto, Stella Trompet, Andre G. Uitterlinden, Matti Uusitupa, Max Vikström, Veronique Vitart, Marie Claude Vohl, Benjamin F. Voight, Peter Vollenweider, Gerard Waeber, Dawn M. Waterworth, Hugh Watkins, Eleanor Wheeler, Elisabeth Widen, Sarah H. Wild, Sara M. Willems, Gonneke Willemsen, James F. Wilson, Jacqueline C.M. Witteman, Alan F. Wright, Hanieh Yaghootkar, Diana Zelenika, Tatijana Zemunik, Lina Zgaga, Nicholas J. Wareham, Mark I. McCarthy, Ines Barroso, Richard M. Watanabe, Jose C. Florez, José Dupuis, James B. Meigs, Claudia Langenberg

Research output: Contribution to journalArticle

444 Scopus citations

Abstract

Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and β-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 × 10 -8 in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.

Original languageEnglish (US)
Pages (from-to)659-669
Number of pages11
JournalNature Genetics
Volume44
Issue number6
DOIs
StatePublished - Jun 2012

ASJC Scopus subject areas

  • Genetics

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    Manning, A. K., Hivert, M. F., Scott, R. A., Grimsby, J. L., Bouatia-Naji, N., Chen, H., Rybin, D., Liu, C. T., Bielak, L. F., Prokopenko, I., Amin, N., Barnes, D., Cadby, G., Hottenga, J. J., Ingelsson, E., Jackson, A. U., Johnson, T., Kanoni, S., Ladenvall, C., ... Langenberg, C. (2012). A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance. Nature Genetics, 44(6), 659-669. https://doi.org/10.1038/ng.2274