Large quantitative effect of melanocortin-4 receptor gene mutations on body mass index

Melanocortin-4 receptor gene (MC4R) mutations are known to cause obesity. The usual practice of ascertaining extremely obese probands to enhance the probability of detecting mutation carriers potentially leads to an overestimation of the phenotypic effects of these mutations. Our aim is to provide a more valid estimate of the effect of MC4R mutations by comparing the body weights of relatives of MC4R mutation carriers, comprising 181 phenotypically unselected relatives of extremely obese index patients from 25 pedigrees. Carriers of functionally relevant mutations had a significantly higher current body mass index (BMI) than their wild type relatives. The observed effect was about twice as strong in females than in males, with BMI differences between mutation carriers and wild type relatives of approximately 2.5 and 1.3 SD, amounting to 9.5 and 4 kg/m(2) in middle aged women and men, respectively. Our findings clearly substantiate that MC4R mutations entail a strong predisposition to obesity. Both the high rate and the degree of adiposity among wild type relatives nevertheless suggest that other genetic and/or environmental effects contribute to the obesity seen in mutation carriers.