Do changes in DNA methylation mediate or interact with SNP variation? A pharmacoepigenetic analysis

BACKGROUND: In studies with multi-omics data available, there is an opportunity to investigate interdependent mechanisms of biological causality. The GAW20 data set includes both DNA genotype and methylation measures before and after fenofibrate treatment. Using change in triglyceride (TG) levels pre- to posttreatment as outcome, we present a mediation analysis that incorporates methylation. This approach allows us to simultaneously consider a mediation hypothesis that genotype affects change in TG level by means of its effect on methylation, and an interaction hypothesis that the effect of change in methylation on change in TG levels differs by genotype. We select 322 single-nucleotide polymorphism–cytosine-phosphate-guanine (SNP-CpG) site pairs for mediation analysis on the basis of proximity and marginal genome-wide association study (GWAS) and epigenome-wide association study (EWAS) significance, and present results from the real-data sample of 407 individuals with complete genotype, methylation, TG levels, and covariate data. RESULTS: We identified 3 SNP-CpG site pairs with significant interaction effects at a Bonferroni-corrected significance threshold of 1.55E-4. None of the analyzed sites showed significant evidence of mediation. Power analysis by simulation showed that a sample size of at least 19,500 is needed to detect nominally significant indirect effects with true effect sizes equal to the point estimates at the locus with strongest evidence of mediation. CONCLUSIONS: These results suggest that there is stronger evidence for interaction between genotype and methylation on change in triglycerides than for methylation mediating the effect of genotype.