A genetic variant in CREBRF, common in Samoans, has an effect size much larger than that of the main BMI-risk-associated variant in FTO, according to a new study. In a genome-wide association study of 3,072 Samoans, the missense CREBRF variant rs373863828 (Arg457Gln) was strongly associated with BMI (P = 7.0 × 10−13), with each copy of the A allele of this variant increasing BMI by 1.36 kg/m2. The A allele of rs373863828 was also associated with an increased risk of obesity (OR = 1.305) and indices of total and regional adiposity (percentage body fat and both abdominal and hip circumference). Overexpression of the Arg457Gln variant in 3T3-L1 mouse adipocytes increased fat storage and decreased energy use. The findings are consistent with rs373863828 being a 'thrifty' variant that promotes disease (obesity) in times of food excess yet affords metabolic advantages in times of food shortage.