Copy number variation on chromosome 10q26.3 for obesity identified by a genome-wide study

Background: Obesity is a highly heritable disease defined by high body mass index (BMI). However, a large proportion of the heritability of obesity remains unexplained. Copy number variations (CNVs) might contribute to the missing heritability of obesity. Methods: We conducted genome-wide CNV analyses on obesity phenotypes, including BMI and body fat mass in a discovery sample of 2215 unrelated white subjects. After quality control, 314 CNVs were used for association tests. For significant CNVs identified, follow-up replication analyses were performed in three independent samples, including an unrelated sample of 1000 white subjects (OM sample), a family-based sample of 8385 white subjects (FHS sample), and an African- American sample of 1479 obesity cases and 1575 lean controls (AA sample). Results: Genome-wide CNV analyses detected that a CNV located at 10q26.3, which, even after multiple testing corrections, showed a strong association with both BMI(P = 2.30 × 10^-4, β = 2.164) and body fat mass (P = 6.76 × 10^-5, β = 4.126). This CNV was successfully replicated in the three replication samples (OM sample: P = 0.0465 for BMI, 0.0435 for fat mass; FHS sample: P = 0.0038 for BMI; AA sample: P = 0.0023 for obesity). Quantitative PCR validated this CNV, which covers a gene, CYP2E1. The protein encoded by CYP2E1 involves the synthesis of cholesterol, steroids and other lipids, which may have a potential impact on obesity. Conclusion: Our findings suggest the significant contribution of CNV10q26.3 to the pathogenesis of obesity.