Identification of influential probe types in epigenetic predictions of human traits: implications for microarray design

Abstract

Background: CpG methylation levels can help to explain inter-individual differences in phenotypic traits. Few studies have explored whether identifying probe subsets based on their biological and statistical properties can maximise predictions whilst minimising array content. Variance component analyses and penalised regression (epigenetic predictors) were used to test the influence of (i) the number of probes considered, (ii) mean probe variability and (iii) methylation QTL status on the variance captured in eighteen traits by blood DNA methylation. Training and test samples comprised ≤ 4450 and ≤ 2578 unrelated individuals from Generation Scotland, respectively. Results: As the number of probes under consideration decreased, so too did the estimates from variance components and prediction analyses. Methylation QTL status and mean probe variability did not influence variance components. However, relative effect sizes were 15% larger for epigenetic predictors based on probes with known or reported methylation QTLs compared to probes without reported methylation QTLs. Relative effect sizes were 45% larger for predictors based on probes with mean Beta-values between 10 and 90% compared to those based on hypo- or hypermethylated probes (Beta-value ≤ 10% or ≥ 90%). Conclusions: Arrays with fewer probes could reduce costs, leading to increased sample sizes for analyses. Our results show that reducing array content can restrict prediction metrics and careful attention must be given to the biological and distribution properties of CpG probes in array content selection.