title: A thrifty variant in CREBRF strongly influences body mass index in Samoans.
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.
authors.affiliation: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Ryan L
authors.initials: RL
authors.lastname: Minster
authors.affiliation: Department of Epidemiology (Chronic Disease), Yale University School of Public Health, New Haven, Connecticut, USA.
authors.forename: Nicola L
authors.initials: NL
authors.lastname: Hawley
authors.affiliation: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Chi-Ting
authors.initials: CT
authors.lastname: Su
authors.affiliation: Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Guangyun
authors.initials: G
authors.lastname: Sun
authors.affiliation: Division of Endocrinology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Erin E
authors.initials: EE
authors.lastname: Kershaw
authors.affiliation: Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Cheng
authors.affiliation: Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Olive D
authors.initials: OD
authors.lastname: Buhule
authors.affiliation: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Jerome
authors.initials: J
authors.lastname: Lin
authors.affiliation: Bureau of Statistics, Government of Samoa, Apia, Samoa.
authors.forename: Muagututi'a Sefuiva
authors.initials: MS
authors.lastname: Reupena
authors.affiliation: Samoa National Health Service, Apia, Samoa.
authors.forename: Satupa'itea
authors.initials: S
authors.lastname: Viali
authors.affiliation: Department of Health, American Samoa Government, Pago Pago, American Samoa, USA.
authors.forename: John
authors.initials: J
authors.lastname: Tuitele
authors.affiliation: Ministry of Health, Government of Samoa, Apia, Samoa.
authors.forename: Take
authors.initials: T
authors.lastname: Naseri
authors.affiliation: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Urban
authors.affiliation: Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Ranjan
authors.initials: R
authors.lastname: Deka
authors.affiliation: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.|Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Weeks
authors.affiliation: International Health Institute, Department of Epidemiology, Brown University School of Public Health, Providence, Rhode Island, USA.|Department of Anthropology, Brown University, Providence, Rhode Island, USA.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: McGarvey
mesh_terms: D000328:Adult; D015992:Body Mass Index; D004734:Energy Metabolism; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008137:Longitudinal Studies; D020125:Mutation, Missense / Q000235:genetics*; D009765:Obesity / Q000453:epidemiology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D018947:Samoa / Q000453:epidemiology; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: C000617553:CREB3 regulatory factor, human; D025521:Tumor Suppressor Proteins