Common variants near MC4R are associated with fat mass, weight and risk of obesity
Loos RJF., Lindgren CM., Li S., Wheeler E., Hua Zhao J., Prokopenko I., Inouye M., Freathy RM., Attwood AP., Beckmann JS., Berndt SI., Bergmann S., Bennett AJ., Bingham SA., Bochud M., Brown M., Cauchi S., Connell JM., Cooper C., Davey Smith G., Day I., Dina C., De S., Dermitzakis ET., Doney ASF., Elliott KS., Elliott P., Evans DM., Sadaf Farooqi I., Froguel P., Ghori J., Groves CJ., Gwilliam R., Hadley D., Hall AS., Hattersley AT., Hebebrand J., Heid IM., Herrera B., Hinney A., Hunt SE., Jarvelin MR., Johnson T., Jolley JDM., Karpe F., Keniry A., Khaw KT., Luben RN., Mangino M., Marchini J., McArdle WL., McGinnis R., Meyre D., Munroe PB., Morris AD., Ness AR., Neville MJ., Nica AC., Ong KK., O'Rahilly S., Owen KR., Palmer CNA., Papadakis K., Potter S., Pouta A., Qi L., Randall JC., Rayner NW., Ring SM., Sandhu MS., Scherag A., Sims MA., Song K., Soranzo N., Speliotes EK., Syddall HE., Teichmann SA., Timpson NJ., Tobias JH., Uda M., Ganz Vogel CI., Wallace C., Waterworth DM., Weedon MN., Willer CJ., Wraight VL., Yuan X., Zeggini E., Hirschhorn JN., Strachan DP., Ouwehand WH., Caulfield MJ., Samani NJ., Frayling TM., Vollenweider P., Waeber G., Mooser V., Deloukas P., McCarthy MI., Wareham NJ.
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. © 2008 Nature Publishing Group.