title: Genome-wide association scans identified CTNNBL1 as a novel gene for obesity.
abstract: Obesity is a major public health problem with strong genetic determination; however, the genetic factors underlying obesity are largely unknown. In this study, we performed a genome-wide association scan for obesity by examining approximately 500 000 single-nucleotide polymorphisms (SNPs) in a sample of 1000 unrelated US Caucasians. We identified a novel gene, CTNNBL1, which has multiple SNPs associated with body mass index (BMI) and fat mass. The most significant SNP, rs6013029, achieved experiment-wise P-values of 2.69 x 10(-7) for BMI and of 4.99 x 10(-8) for fat mass, respectively. The SNP rs6013029 minor allele T confers an average increase in BMI and fat mass of 2.67 kg/m(2) and 5.96 kg, respectively, compared with the alternative allele G. We further genotyped the five most significant CTNNBL1 SNPs in a French case-control sample comprising 896 class III obese adults (BMI > or = 40 kg/m(2)) and 2916 lean adults (BMI < 25 kg/m(2)). All five SNPs showed consistent associations with obesity (8.83 x 10(-3) < P < 6.96 x 10(-4)). Those subjects who were homozygous for the rs6013029 T allele had 1.42-fold increased odds of obesity compared with those without the T allele. The protein structure of CTNNBL1 is homologous to beta-catenin, a family of proteins containing armadillo repeats, suggesting similar biological functions. beta-Catenin is involved in the Wnt/beta-catenin-signaling pathway which appears to contribute to maintaining the undifferentiated state of pre-adipocytes by inhibiting adipogenic gene expression. Our study hence suggests a novel mechanism for the development of obesity, where CTNNBL1 may play an important role. Our study also provided supportive evidence for previously identified associations between obesity and INSIG2 and PFKP, but not FTO.
authors.affiliation: School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA.
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Liu
authors.forename: Xiao-Gang
authors.initials: XG
authors.lastname: Liu
authors.forename: Liang
authors.initials: L
authors.lastname: Wang
authors.forename: Christian
authors.initials: C
authors.lastname: Dina
authors.forename: Han
authors.initials: H
authors.lastname: Yan
authors.forename: Jian-Feng
authors.initials: JF
authors.lastname: Liu
authors.forename: Shawn
authors.initials: S
authors.lastname: Levy
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Papasian
authors.forename: Betty M
authors.initials: BM
authors.lastname: Drees
authors.forename: James J
authors.initials: JJ
authors.lastname: Hamilton
authors.forename: David
authors.initials: D
authors.lastname: Meyre
authors.forename: Jerome
authors.initials: J
authors.lastname: Delplanque
authors.forename: Yu-Fang
authors.initials: YF
authors.lastname: Pei
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Robert R
authors.initials: RR
authors.lastname: Recker
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
authors.forename: Hong-Wen
authors.initials: HW
authors.lastname: Deng
mesh_terms: D016022:Case-Control Studies; D005260:Female; D005602:France; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006801:Humans; D008297:Male; D008875:Middle Aged; D009329:Nebraska; D009765:Obesity / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics