Abstract
BackgroundWe conducted an epigenome-wide association study (EWAS) on obesity in healthy youth and young adults and further examined to what extent identified signals influenced gene expression and were independent of cell type composition and obesity-related cardio-metabolic risk factors. Genome-wide DNA methylation data from leukocytes were obtained from 700 African Americans aged 14–36. We also measured genome-wide DNA methylation data from neutrophils as well as genome-wide gene expression data from leukocytes in a subset of samples (n = 188).ResultsThe EWAS identified 76 obesity-related CpG sites in leukocytes with p < 1 × 10−7. In silico replication in the ARIC study of 2097 African Americans aged 47–70 validated 54 CpG sites. Out of the 54 CpG sites, 29 associations with obesity were novel and 37 were replicated in neutrophils. Fifty one CpG sites were associated with at least one cardio-metabolic risk factor; however, the number reduced to 9 after adjustment for obesity. Sixteen CpG sites were associated with expression of 17 genes in cis, of which 5 genes displayed differential expression between obese cases and lean controls. We also replicated 71.5% of obesity-related CpG sites previously reported.ConclusionIn this study of youth and young adults, we identified 29 novel CpG sites associated with obesity and replicated the majority of the CpG sites previously identified. We further demonstrated that the majority of the obesity-related CpG sites in leukocytes were not driven by cell composition or obesity-related cardio-metabolic risk factors. We also provided the direct link between DNA methylation-gene expression-obesity for 5 genes.
Highlights
We conducted an epigenome-wide association study (EWAS) on obesity in healthy youth and young adults and further examined to what extent identified signals influenced gene expression and were independent of cell type composition and obesity-related cardio-metabolic risk factors
Wang et al Clinical Epigenetics (2018) 10:3 new signals and further validate the findings with replication in an independent cohort of 2097 middle-aged African Americans from the Atherosclerosis Risk in Communities (ARIC) study [2]. For these obesityrelated Deoxyribonucleic acid (DNA) methylation loci, we checked whether the associations can be replicated in one purified cell type, whether the associations were driven by obesity-related cardio-metabolic traits, and whether the DNA methylation status of these loci was associated with gene expressions
We identified 76 CpG sites significantly associated (p < 1 × 10 −07) with obesity in the meta-analysis of the three cohorts (Manhattan and QQ-plot, Fig. 1; Additional file 2: Table S1)
Summary
We conducted an epigenome-wide association study (EWAS) on obesity in healthy youth and young adults and further examined to what extent identified signals influenced gene expression and were independent of cell type composition and obesity-related cardio-metabolic risk factors. Wang et al Clinical Epigenetics (2018) 10:3 new signals and further validate the findings with replication in an independent cohort of 2097 middle-aged African Americans from the Atherosclerosis Risk in Communities (ARIC) study [2]. For these obesityrelated DNA methylation loci, we checked whether the associations can be replicated in one purified cell type (neutrophils), whether the associations were driven by obesity-related cardio-metabolic traits, and whether the DNA methylation status of these loci was associated with gene expressions. The identification of obesity-related DNA methylation changes in youth and young adult may provide new insights into the mechanisms linking obesity to associated clinical conditions at the early stages of the disease process and may provide new targets for early prevention
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