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, Sven Bergmann, Amanda J Bennett, Sheila A. Bingham, Murielle Bochud, Morris Brown, Stephane Cauchi, John M. Connell, Cyrus Cooper, George Davey SmithIan Day, Christian Dina, Subhajyoti De, Emmanouil T. Dermitzakis, A Doney, Paul Elliott, Katherine S. 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, 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, Wellcome Trust Case Control Consortium, Nurses' Health Study, FUSION, Diabetes Genetics Initiative, SardiNIA Study, Prostate Lung Colorectal Ovarian, KORA

Research output: Contribution to journalArticlepeer-review

1052 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)768-775
Number of pages8
JournalNature Genetics
Issue number6
Early online date4 May 2008
Publication statusPublished - Jun 2008


  • genome-wide association
  • melanocortin-4 receptor gene
  • early-onset obesity
  • frameshift mutation
  • adult obesity
  • expression
  • deficiency
  • childhood
  • dominant
  • humans


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