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

Loos, Ruth J F, Lindgren, Cecilia M, Li, Shengxu, Wheeler, Eleanor, Zhao, Jing Hua, Prokopenko, Inga, Inouye, Michael, Freathy, Rachel M, Attwood, Antony P, Beckmann, Jacques S, Berndt, Sonja I, Jacobs, Kevin B, Chanock, Stephen J, Hayes, Richard B, Bergmann, Sven, Bennett, Amanda J, Bingham, Sheila A, Bochud, Murielle, Brown, Morris, Cauchi, Stéphane, Connell, John M, Cooper, Cyrus, Smith, George Davey, Day, Ian, Dina, Christian, De, Subhajyoti, Dermitzakis, Emmanouil T, Doney, Alex S F, Elliott, Katherine S, Elliott, Paul, Evans, David M, Sadaf Farooqi, I, Froguel, Philippe, Ghori, Jilur, Groves, Christopher J, Gwilliam, Rhian, Hadley, David, Hall, Alistair S, Hattersley, Andrew T, Hebebrand, Johannes, Heid, Iris M, Lamina, Claudia, Gieger, Christian, Illig, Thomas, Meitinger, Thomas, Wichmann, H-Erich, Herrera, Blanca, Hinney, Anke, Hunt, Sarah E, Jarvelin, Marjo-Riitta, Johnson, Toby, Jolley, Jennifer D M, Karpe, Fredrik, Keniry, Andrew, Khaw, Kay-Tee, Luben, Robert N, Mangino, Massimo, Marchini, Jonathan, McArdle, Wendy L, McGinnis, Ralph, Meyre, David, Munroe, Patricia B, Morris, Andrew D, Ness, Andrew R, Neville, Matthew J, Nica, Alexandra C, Ong, Ken K, O'Rahilly, Stephen, Owen, Katharine R, Palmer, Colin N A, Papadakis, Konstantinos, Potter, Simon, Pouta, Anneli, Qi, Lu, Kraft, Peter, Hankinson, Susan E, Hunter, David J, Hu, Frank B, Randall, Joshua C, Rayner, Nigel W, Ring, Susan M, Sandhu, Manjinder S, Scherag, André, Sims, Matthew A, Song, Kijoung, Soranzo, Nicole, Speliotes, Elizabeth K, Lyon, Helen N, Voight, Benjamin F, Ridderstrale, Martin, Groop, Leif, Syddall, Holly E, Teichmann, Sarah A, Timpson, Nicholas J, Tobias, Jonathan H, Uda, Manuela, Scheet, Paul, Sanna, Serena, Abecasis, Goncalo R, Albai, Giuseppe, Nagaraja, Ramaiah, Schlessinger, David, Ganz Vogel, Carla I, Wallace, Chris, Waterworth, Dawn M, Weedon, Michael N, Willer, Cristen J, Jackson, Anne U, Tuomilehto, Jaakko, Collins, Francis S, Boehnke, Michael, Mohlke, Karen L, Wraight, Vicki L, Yuan, Xin, Zeggini, Eleftheria, Hirschhorn, Joel N, Strachan, David P, Ouwehand, Willem H, Caulfield, Mark J, Samani, Nilesh J, Frayling, Timothy M, Vollenweider, Peter, Waeber, Gerard, Mooser, Vincent, Deloukas, Panos, McCarthy, Mark I, Wareham, Nicholas J, Barroso, Inês, Fraser, Christine, Green, Elaine, Grozeva, Detelina, Hamshere, Marian Lindsay ORCID:, Holmans, Peter Alan ORCID:, Jones, Ian Richard ORCID:, Kirov, George ORCID:, Escott-Price, Valentina ORCID:, Nikolov, Ivan, O'Donovan, Michael Conlon ORCID:, Owen, Michael John ORCID: and Craddock, Nicholas John ORCID: 2008. Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nature Genetics 40 (6) , pp. 768-775. 10.1038/ng.140

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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 x 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 x 10(-15)) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 x 10(-8)). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 x 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 x 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Neuroscience and Mental Health Research Institute (NMHRI)
Subjects: R Medicine > R Medicine (General)
Additional Information: Christine Fraser, Elaine Green, Detelina Grozeva, Marian Hamshere, Peter Holmans, Ian Jones, George Kirov, Valentina Moskvina, Ivan Nikolov, Michael O'Donovan, Michael Owen and Nick Craddock are collaborators on this article.
Publisher: Nature Publishing Group
ISSN: 1061-4036
Last Modified: 17 Aug 2023 18:30

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