Epigenome-wide study identifies novel methylation loci associated with body mass index and waist circumference

OBJECTIVE: To conduct an epigenome-wide analysis of DNA methylation and obesity traits. DESIGN AND METHODS: We quantified DNA methylation in CD4+ T-cells using the Illumina Infinium Human Methylation450 array in 991 participants of the Genetics of Lipid Lowering Drugs and Diet Network. We modeled methylation at individual cytosine-phosphate-guanine (CpG) sites as a function of body mass index (BMI) and waist circumference (WC), adjusting for age, gender, study site, T-cell purity, smoking, and family structure. RESULTS: We found epigenome-wide significant associations between eight CpG sites and BMI and five CpG sites and WC, successfully replicating the top hits in whole blood samples from the Framingham Heart Study (n=2,377) and the Atherosclerosis Risk in Communities study (n=2,105). Top findings were in CPT1A (meta-analysis P= 3.5×10(−37) for BMI and P=2.2×10(−16) for WC), PHGDH (meta-analysis P= 4.7×10(−15) for BMI and 2.2×10(−8) for WC), CD38 (meta-analysis P= 3.7×10(−11) for BMI and 6.1×10(−13) for WC) and long intergenic non-coding RNA 00263 (meta-analysis P= 1.2×10(−13) for BMI and 5.8×10(−10) for WC), regions with biologically plausible relationships to adiposity. CONCLUSIONS: This large-scale epigenome-wide study discovered and replicated robust associations between DNA methylation at CpG loci and obesity indices, laying the groundwork for future diagnostic and/or therapeutic applications.