Common variants near MC4R are associated with fat mass, weight and risk of obesity

Ruth J F Loos, Cecilia M. Lindgren, Shengxu Li, Eleanor Wheeler, Jing Hua Zhao, Inga Prokopenko, Michael Inouye, Rachel M. Freathy, Antony P. Attwood, Jacques S. Beckmann, Sonja I. Berndt, Kevin B. Jacobs, Stephen J. Chanock, Richard B. Hayes, Sven Bergmann, Amanda J. Bennett, Sheila A. Bingham, Murielle Bochud, Morris Brown, Stéphane CauchiJohn M. Connell, Cyrus Cooper, George Davey Smith, Ian Day, Christian Dina, Subhajyoti De, Emmanouil T. Dermitzakis, Alex S F Doney, Katherine S. Elliott, Paul Elliott, David M. Evans, I. Sadaf Farooqi, Philippe Froguel, Jilur Ghori, Christopher J. Groves, Rhian Gwilliam, David Hadley, Alistair S. Hall, Andrew T. Hattersley, Johannes Hebebrand, Iris M. Heid, Claudia Lamina, Christian Gieger, Thomas Illig, Thomas Meitinger, H. Erich Wichmann, Blanca Herrera, Anke Hinney, Sarah E. Hunt, Marjo Riitta Jarvelin, Toby Johnson, Jennifer D M Jolley, Fredrik Karpe, Andrew Keniry, Kay Tee Khaw, Robert N. Luben, Massimo Mangino, Jonathan Marchini, Wendy L. McArdle, Ralph McGinnis, David Meyre, Patricia B. Munroe, Andrew D. Morris, Andrew R. Ness, Matthew J. Neville, Alexandra C. Nica, Ken K. Ong, Stephen O'Rahilly, Katharine R. Owen, Colin N A Palmer, Konstantinos Papadakis, Simon Potter, Anneli Pouta, Lu Qi, Peter Kraft, Susan E. Hankinson, David J. Hunter, Frank B. Hu, Joshua C. Randall, Nigel W. Rayner, Susan M. Ring, Manjinder S. Sandhu, André Scherag, Matthew A. Sims, Kijoung Song, Nicole Soranzo, Elizabeth K. Speliotes, Helen N. Lyon, Benjamin F. Voight, Martin Ridderstrale, Leif Groop, Holly E. Syddall, Sarah A. Teichmann, Nicholas J. Timpson, Jonathan H. Tobias, Manuela Uda, Paul Scheet, Serena Sanna, Goncalo R. Abecasis, Giuseppe Albai, Ramaiah Nagaraja, David Schlessinger, Carla I. Ganz Vogel, Chris Wallace, Dawn M. Waterworth, Michael N. Weedon, Cristen J. Willer, Anne U. Jackson, Jaakko Tuomilehto, Francis S. Collins, Michael Boehnke, Karen L. Mohlke, Vicki L. Wraight, Xin Yuan, Eleftheria Zeggini, Joel N. Hirschhorn, David P. Strachan, Willem H. Ouwehand, Mark J. Caulfield, Nilesh J. Samani, Timothy M. Frayling, Peter Vollenweider, Gerard Waeber, Vincent Mooser, Panos Deloukas, Mark I. McCarthy, Nicholas J. Wareham, Inês Barroso

Research output: Contribution to journalLetterpeer-review

Abstract

To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 × 10-6) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 × 10 -15) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 × 10-8). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 × 10-11). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) = 2.4 × 10-4). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits.

Original languageEnglish
Pages (from-to)768-775
Number of pages8
JournalNature Genetics
Volume40
Issue number6
DOIs
Publication statusPublished - 1 Jun 2008

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