Several risk alleles in MC4R, which are common and consistently associated with obesity/BMI in studies of Caucasians (e.g., rs17782313, rs17700633 and rs571312), are uncommon in American Indians (frequency = 0.03, 0.005 and 0.003, respectively) despite American Indians having much higher rates of obesity than Caucasians. Here, MC4R is linked to obesity due to melanocortin 4 receptor deficiency.