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

Abstract

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.

Association of Body Mass Index with DNA Methylation and Gene Expression in Blood Cells and Relations to Cardiometabolic Disease: A Mendelian Randomization Approach

“…DHCR24 (24-dehydrocholesterol reductase) catalyzes the reduction of sterol intermediates during cholesterol synthesis. Differential methylation of SREBF1, CPT1A, ABCG1, and DHCR24 has been reported in previous EWASs of adiposity, glycemic traits, and lipids [29][30][31][71][72][73][74][75][76]. We add to the published literature and provide evidence that differential methylation at the ABCG1 locus is likely a downstream effect of BMI.…”

“…The majority of BMI-related CpGs (65%-85% of CpGs depending on the cohort) had mean sample CpG methylation levels between 20% and 80% (S4 Table). Fifty of the 83 replicated differentially methylated CpGs have not been previously reported in microarraybased EWASs of BMI [28][29][30][31][32][33][34][35][36] (Table 3). Age and sex interactions among the BMI EWAS findings.…”

The Omics of Obesity

“…They also identified four differentially methylated sites associated with waist circumference Cg00574958 (CPT1A), Cg04332373 (CD38), Cg14476101 (PHGDH) and cg25349939 (GTDC1) [36]. They replicated these methylation sites in whole blood from two independent cohorts-the Framingham Heart Study (FHS) (n = 1,935 case: control study, and n = 442 random samples) and the Atherosclerosis Risk in Communities (ARIC) study (n = 2,015 samples).…”

An Epigenome-Wide Association Study of Inflammatory Response to Fenofibrate in the Genetics of Lipid Lowering Drugs and Diet Network

“…Random subsets of 10,000 CpGs per run were run after normalization, in which each array of 12 samples were used as batch. Correction for differing probe chemistry was performed on Illumina Infinium HumanMethylation450 Bead chip, normalizing the probes separately from the Infinium I and II [26][27]29,31].…”