In humans, multiple rare mutations conferring loss of function in the MC4R gene are associated with hyperphagia, severe childhood obesity and hyperinsulinemia.45 Experimental studies show that MC4R is a key regulator of energy balance, influencing food intake and energy expenditure through functionally divergent central melanocortin neuronal pathways.46 MC4R contains two SNPs that were significantly associated with BMI in our study. The rs477181 and rs4450508 are located in the same LD block (D’ = 0.97) at chromosome 18q21, with effect sizes of 0.05 and=0.04 s.d. unit of BMI, respectively. Although the G-allele of rs477181 was associated with BMI in both the Europeans and our African-American samples, however, the direction of association for rs4450508 differs between the two populations (Supplementary Table 4).
