Environmental Exposure and DNA Damage

National Institute Of Environmental Health Sciences

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Abstract

Illumina BeadChips are widely utilized in epigenome-wide association studies (EWAS). Several studies have reported that many probes on these arrays have poor reliability. We compared different pre-processing methods to improve intra-class correlation coefficients (ICC). Using technical duplicates from 128 subjects, we find that with raw data only 22.5% of the CpGs on 450 K array have 'acceptable' ICCs (>0.5). ICC is associated with CpG methylation level such that 83% of CpGs with intermediate methylation (0.1< beta-value <0.9) have acceptable ICCs, whereas only 21% of CpGs with low or high methylation (beta-value <0.1 or >0.9) have acceptable ICCs. Many CpGs with poor ICCs (<0.5) are located in biologically important regulatory regions, including gene promoters and CpG islands. Data preprocessing steps, such as background correction and dye bias correction, can reduce technical noise and improve the percentage of CpGs with acceptable ICC to 38.5%. Although individual CpGs may have weak association, there is growing evidence that spatially clustered CpGs or differentially methylated regions (DMRs) may have stronger associations with disease. A variety of methods have been introduced that combine information from adjacent CpGs to identify DMRs one of the most effective methods being comb-p. We developed a new method ipDMR that identifies DMRs based on user-provided association P-values for individual CpGs and compare it to comb-p under a variety of conditions, showing that ipDMR has a higher rate for finding true positive DMR while having a much lower rate for identifying false DMRs and is computationally more efficient. We provide software implementations for both methods in our publicly-avaiable ENmix software suite. Epigenetic age acceleration is considered a measure of biological aging based on genome-wide patterns of DNA methylation. Although age acceleration has been associated with incidence of diseases and death, less is known about how it is related to lifestyle behaviors. Among 2,316 women, we evaluate associations between self-reported alcohol consumption and various metrics of epigenetic age acceleration using four epigenetic clocks (Hannum, Horvath, PhenoAge, GrimAge) and their corresponding metrics of epigenetic age acceleration (Hannum AgeAccel, Horvath AgeAccel, PhenoAgeAccel, GrimAgeAccel). We find that although alcohol use does not appear to be strongly associated with biological age measured by most epigenetic clocks, lifetime average consumption is associated with higher biological age assessed by the GrimAge epigenetic clockan epigenetic clock specifically developed to predict mortality risk. Using these same four clocks we also examined associations with self-reported physical activity and several measures of body composition. all adiposity measures were associated with epigenetic age acceleration: The strongest association was for body mass index (BMI) and PhenoAge, a measure of biological age that correlates with chronic disease, while physical activity was inversely associated with GrimAge.