Journal Article

Genome-wide association scans identified <i>CTNNBL1</i> as a novel gene for obesity

Yong-Jun Liu, Xiao-Gang Liu, Liang Wang, Christian Dina, Han Yan, Jian-Feng Liu, Shawn Levy, Christopher J. Papasian, Betty M. Drees, James J. Hamilton, David Meyre, Jerome Delplanque, Yu-Fang Pei, Lei Zhang, Robert R. Recker, Philippe Froguel and Hong-Wen Deng

in Human Molecular Genetics

Volume 17, issue 12, pages 1803-1813
Published in print June 2008 | ISSN: 0964-6906
Published online March 2008 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddn072
Genome-wide association scans identified CTNNBL1 as a novel gene for obesity

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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 × 10−7 for BMI and of 4.99 × 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/m2 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 ≥ 40 kg/m2) and 2916 lean adults (BMI < 25 kg/m2). All five SNPs showed consistent associations with obesity (8.83 × 10−3 < P < 6.96 × 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 β-catenin, a family of proteins containing armadillo repeats, suggesting similar biological functions. β-Catenin is involved in the Wnt/β-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.

Journal Article.  6336 words.  Illustrated.

Subjects: Genetics and Genomics

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