Abstract
BackgroundModification of DNA by methylation of cytosines at CpG dinucleotides is a widespread phenomenon that leads to changes in gene expression, thereby influencing and regulating many biological processes. Recent technical advances in the genome-wide determination of single-base DNA-methylation enabled epigenome-wide association studies (EWASs). Early EWASs established robust associations between age and gender with the degree of CpG methylation at specific sites. Other studies uncovered associations with cigarette smoking. However, so far these studies were mainly conducted in Caucasians, raising the question of whether these findings can also be extrapolated to other populations.ResultsHere, we present an EWAS with age, gender, and smoking status in a family study of 123 individuals of Arab descent. We determined DNA methylation at over 450,000 CpG sites using the Illumina Infinium HumanMethylation450 BeadChip, applied state-of-the-art data processing protocols, including correction for blood cell type heterogeneity and hidden confounders, and eliminated probes containing SNPs at the targeted CpG site using 40× whole-genome sequencing data. Using this approach, we could replicate the leading published EWAS associations with age, gender and smoking, and recovered hallmarks of gender-specific epigenetic changes. Interestingly, we could even replicate the recently reported precise prediction of chronological age based on the methylation of only a few selected CpG sites.ConclusionOur study supports the view that when applied with state-of-the art protocols to account for all potential confounders, DNA methylation arrays represent powerful tools for EWAS with more complex phenotypes that can also be successfully applied to non-Caucasian populations.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-014-0040-6) contains supplementary material, which is available to authorized users.
Highlights
Modification of DNA by methylation of cytosines at CpG dinucleotides is a widespread phenomenon that leads to changes in gene expression, thereby influencing and regulating many biological processes
Initial contacts with probands were made through their regular follow-up visits to the Qatar Diabetes Association (QDA), a secondary health-care center that provides patients care, education, and support
Smoking-related differential methylation To identify the relevant covariates to include into the final model, we evaluated the effect of including the estimated white blood cell coefficients and the principal components (PCs) on the p value distribution
Summary
Modification of DNA by methylation of cytosines at CpG dinucleotides is a widespread phenomenon that leads to changes in gene expression, thereby influencing and regulating many biological processes. A CpG site is a DNA region where a cytosine nucleotide is found next to a guanine in the genome sequence, connected by a phosphate group This process is catalyzed by a number of DNA methyltransferase enzymes [1]. One of the main roles of epigenetic modifications through DNA methylation is to control gene transcription in response to external and internal stimuli by targeting specific regulatory DNA bases, such as promoter and enhancer regions [7,8,9]. Another important biological process that is controlled by DNA methylation is the maintenance of gene imprinting [10]. It was shown that the majority of this genome-wide demethylation is complete at the two-cell stage and that the demethylation process is much faster in males than in females [13]
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