Human Molecular Genetics Advance Access originally published online on March 5, 2008
Human Molecular Genetics 2008 17(12):1803-1813; doi:10.1093/hmg/ddn072
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Genome-wide association scans identified CTNNBL1 as a novel gene for obesity
1 School of Medicine, University of Missouri—Kansas City, Kansas City, MO 64108, USA 2 The Key Laboratory of Biomedical Information Engineering of Ministry of Education and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, P. R. China 3 Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, P. R. China 4 Osteoporosis Research Center, Creighton University, Omaha, NE 68131, USA 5 Vanderbilt Microarray Shared Resource, Vanderbilt University, Nashville, TN 37232, USA 6 CNRS-8090-Institute of Biology, Pasteur Institute, Lille, France 7 Genomic Medicine, Hammersmith Hospital, Imperial College London, London, UK
* To whom correspondence should be addressed at: Department of Basic Medical Science and Department of Orthopedic Surgery, University of Missouri—Kansas City, 2411 Holmes Street, Room M3-C03, Kansas City, MO 64108-2792, USA. Tel: +1 8162355354; Fax: +1 8162356517; Email: dengh{at}umkc.edu
Received August 26, 2007; Accepted March 4, 2008
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/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 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 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.