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

Loos, R. J. F. et al. (2008) Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nature Genetics, 40(6), pp. 768-775. (doi:10.1038/ng.140)

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Publisher's URL: http://dx.doi.org/10.1038/ng.140

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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Herrera, Dr Blanca and Connell, Professor John
Authors: Loos, R. J. F., Lindgren, C. M., Li, S., Wheeler, E., Zhao, J. H., Prokopenko, I., Inouye, M., Freathy, R. M., Attwood, A. P., Beckmann, J. S., Berndt, S. I., Bergmann, S., Bennett, A. J., Bingham, S. A., Bochud, M., Brown, M., Cauchi, S., Connell, J. M., Cooper, C., Smith, G. D., Day, I., Dina, C., De, S., Dermitzakis, E. T., Doney, A. S. F., Elliott, K. S., Elliott, P., Evans, D. M., Farooqi, I. S., Froguel, P., Ghori, J., Groves, C. J., Gwilliam, R., Hadley, D., Hall, A. S., Hattersly, A. T., Hebebrand, J., Heid, I. M., Herrera, B., Hinney, A., Hunt, S. E., Jarvelin, M.-R., Johnson, T., Jolley, J. D. M., Karpe, F., Keniry, A., Khaw, K.-T., Luben, R. N., Mangino, M., Marchini, J., McArdle, W. L., McGinnis, R., Meyre, D., Munroe, P. B., Morris, A. D., Ness, A. R., Neville, M. J., Nica, A. C., Ong, K. K., O'Rahilly, S., Owen, K. R., Palmer, C. N. A., Papadakis, K., Potter, S., Pouta, A., Qi, L., Randall, J. C., Rayner, N. W., Ring, S. M., Sandhu, M. S., Scherag, A., Sims, M. A., Song, K., Soranzo, N., Speliotes, E. K., Syddall, H. E., Teichmann, S. A., Timpson, N. J., Tobias, J. H., Uda, M., Vogel, C. I. G., Wallace, C., Waterworth, D. M., Weedon, M. N., Willer, C. J., Wraight, V. L., Yuan, X., Zeggini, E., Hirschhorn, J. N., Strachan, D. P., Ouwehand, W. H., Caulfield, M. J., Samani, N. J., Frayling, T. M., Vollenweider, P., Waeber, G., Mooser, V., Deloukas, P., McCarthy, M. I., Wareham, N. J., and Barroso, I.
College/School:College of Medical Veterinary and Life Sciences
Journal Name:Nature Genetics
Publisher:Nature Publishing Group
ISSN:1061-4036
ISSN (Online):1546-1718
Published Online:04 May 2008
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
392521Regulation of aldosterone and cortisol synthesis in hypertension and cardiovascular diseaseEleanor DaviesMedical Research Council (MRC)G0400874Institute of Cardiovascular and Medical Sciences
392522Regulation of aldosterone and cortisol synthesis in hypertension and cardiovascular diseaseEleanor DaviesMedical Research Council (MRC)G0400874Institute of Cardiovascular and Medical Sciences