Genome-wide association scans identified CTNNBL1 as a novel gene for obesity.
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.
Liu
Yong-Jun
YJ
School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA.
Liu
Xiao-Gang
XG
Wang
Liang
L
Dina
Christian
C
Yan
Han
H
Liu
Jian-Feng
JF
Levy
Shawn
S
Papasian
Christopher J
CJ
Drees
Betty M
BM
Hamilton
James J
JJ
Meyre
David
D
Delplanque
Jerome
J
Pei
Yu-Fang
YF
Zhang
Lei
L
Recker
Robert R
RR
Froguel
Philippe
P
Deng
Hong-Wen
HW
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