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, , Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial and Forbes, Alastair (2008) Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nature Genetics, 40 (6). pp. 768-75. ISSN 1061-4036

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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 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
Uncontrolled Keywords: adiposity,adolescent,adult,aged,alleles,body mass index,body weight,case-control studies,child,human chromosomes pair 18,cohort studies,cross-sectional studies,female,genetic predisposition to disease,genetic variation,genome, human,humans,linkage disequilibrium,male,meta-analysis as topic,middle aged,obesity,single nucleotide polymorphism,proteins,quantitative trait loci,randomized controlled trials as topic,melanocortin type 4 receptor
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: Pure Connector
Date Deposited: 06 Aug 2014 11:50
Last Modified: 11 Apr 2019 15:42
URI: https://ueaeprints.uea.ac.uk/id/eprint/49700
DOI: 10.1038/ng.140

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