A thrifty variant in CREBRF strongly influences body mass index in Samoans

Abstract

Samoans are a unique founder population with a high prevalence of obesity1–3, making them well suited for identifying new genetic contributors to obesity4. We conducted a genome-wide association study (GWAS) in 3,072 Samoans, discovered a variant, rs12513649, strongly associated with body mass index (BMI) (P = 5.3 × 10−14), and replicated the association in 2,102 additional Samoans (P = 1.2 × 10−9). Targeted sequencing identified a strongly associated missense variant, rs373863828 (p.Arg457Gln), in CREBRF (meta P = 1.4 × 10−20). Although this variant is extremely rare in other populations, it is common in Samoans (frequency of 0.259), with an effect size much larger than that of any other known common BMI risk variant (1.36–1.45 kg/m2 per copy of the risk-associated allele). In comparison to wild-type CREBRF, the Arg457Gln variant when overexpressed selectively decreased energy use and increased fat storage in an adipocyte cell model. These data, in combination with evidence of positive selection of the allele encoding p.Arg457Gln, support a ‘thrifty’ variant hypothesis as a factor in human obesity.

Going global by adapting local: A review of recent human adaptation

“…Over 80% of Samoans are overweight or obese [body mass index (BMI) > 26 kg/m 2 ], which is among the highest prevalence in the world (36). By genotyping ~3000 Samoans, a missense variant in CREBRF was found to be associated with BMI and fasting glucose levels.…”

Culturally responsive approaches to health promotion for Native Hawaiians and Pacific Islanders

“…The high prevalence of cardiometabolic disorders among NHPI have been attributed to genetic/biological dispositions (Minster et al 2016), lifestyle behaviors (e.g., calorie-dense diet and physical inactivity) (Kolonel et al 2000), socioeconomic deprivation (e.g., lower income and education levels), sociocultural challenges (e.g., colonization and acculturation stressors) (Kaholokula, Nacapoy, and Dang 2009), psychosocial stressors (e.g., discrimination) (Kaholokula, Iwane, and Nacapoy 2010), environmental conditions (Mau et al 2008), and complex permutations of these variables (Kirtland, Cho, and Geiss 2015). Health interventions targeting cardiometabolic disorders in NHPI communities need to be culturally responsive and account for their interpersonal, sociocultural, and socioeconomic realities.…”

The evolution of body fatness: trading off disease and predation risk

“…The gene seems to be linked at a cellular level to adipocyte responses to starvation, and the insertion of the mutation into adipocytes protects them from starvation-induced mortality. Whether this cell-based assay also means that the gene protects people from starvation-induced mortality is unclear, although this was the basis of the claim that the gene variant is 'thrifty' (Minster et al, 2016). If this is shown to be the case, it would be strong evidence that extremely rare 'thrifty genes' favouring survival in famines may exist and be selected for in small populations.…”

“…the shortfall between the known heritability and the proportion explained by common variants. One potential example of such a gene was found in the people living on the island of Samoa in the South Pacific Ocean (Minster et al, 2016). The variant is a mis-sense mutation that results in a coding change in the gene CREBRF.…”