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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/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 ≥ 40 kg/m 2 ) and 2916 lean adults (BMI &lt; 25 kg/m 2 ). All five SNPs showed consistent associations with obesity (8.83 × 10 −3  &lt;  P  &lt; 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 .

Genome-wide association scans identified CTNNBL1 as a novel gene for obesity