Epigenomic elements analyses for promoters identify ESRRG as a new susceptibility gene for obesity-related traits

OBJECTIVES: With ENCODE epigenomic data and results from published genome-wide association studies (GWASs), we aimed to find regulatory signatures of obesity genes and discover novel susceptibility genes. METHODS: Obesity genes were obtained from public GWAS databases and their promoters were annotated based on the regulatory element information. Significantly enriched or depleted epigenomic elements in the promoters of obesity genes were evaluated and all human genes were then prioritized according to the existence of the selected elements to predict new candidate genes. Top-ranked genes were subsequently applied to validate their associations with obesity-related traits in three independent in-house GWAS samples. RESULTS: We identified RAD21 and EZH2 as over-represented, and STAT2 (signal transducer and activator of transcription 2) and IRF3 (interferon regulatory transcription factor 3) as depleted transcription factors. Histone modification of H3K9me3 and chromatin state segmentation of 'poised promoter' and 'repressed' were over-represented. All genes were prioritized and we selected the top five genes for validation at the population level. Combining results from the three GWAS samples, rs7522101 in ESRRG (estrogenrelated receptor-gamma) remained significantly associated with body mass index after multiple testing corrections (P = 7.25 x 10(-5)). It was also associated with beta-cell function (P = 1.99 x 10(-3)) and fasting glucose level (P<0.05) in the meta-analyses of glucose and insulin-related traits consortium (MAGIC) data set. CONCLUSIONS: In summary, we identified epigenomic characteristics for obesity genes and suggested ESRRG as a novel obesity-susceptibility gene.