Format

Send to

Choose Destination
Nat Genet. 2016 Sep;48(9):1049-1054. doi: 10.1038/ng.3620. Epub 2016 Jul 25.

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

Author information

1
Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
2
Department of Epidemiology (Chronic Disease), Yale University School of Public Health, New Haven, Connecticut, USA.
3
Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
4
Division of Endocrinology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
5
Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
6
Bureau of Statistics, Government of Samoa, Apia, Samoa.
7
Samoa National Health Service, Apia, Samoa.
8
Department of Health, American Samoa Government, Pago Pago, American Samoa, USA.
9
Ministry of Health, Government of Samoa, Apia, Samoa.
10
International Health Institute, Department of Epidemiology, Brown University School of Public Health, Providence, Rhode Island, USA.
11
Department of Anthropology, Brown University, Providence, Rhode Island, USA.
#
Contributed equally

Abstract

Samoans are a unique founder population with a high prevalence of obesity, making them well suited for identifying new genetic contributors to obesity. 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/m(2) 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.

PMID:
27455349
PMCID:
PMC5069069
DOI:
10.1038/ng.3620
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center