Incorporation of DNA methylation into eQTL mapping in African Americans.

Epigenetics is a reversible molecular mechanism that plays a critical role in many developmental, adaptive, and disease processes. DNA methylation has been shown to regulate gene expression and the advent of high throughput technologies has made genome-wide DNA methylation analysis possible. We investigated the effect of DNA methylation in eQTL mapping (methylation-adjusted eQTLs), by incorporating DNA methylation as a SNP-based covariate in eQTL mapping in African American derived hepatocytes. We found that the addition of DNA methylation uncovered new eQTLs and eGenes. Previously discovered eQTLs were significantly altered by the addition of DNA methylation data suggesting that methylation may modulate the association of SNPs to gene expression. We found that methylation-adjusted eQTLs which were less significant compared to PC-adjusted eQTLs were enriched in lipoprotein measurements (FDR = 0.0040), immune system disorders (FDR = 0.0042), and liver enzyme measurements (FDR = 0.047), suggesting a role of DNA methylation in regulating the genetic basis of these phenotypes. Our methylation-adjusted eQTL analysis also uncovered novel SNP-gene pairs. For example, our study found the SNP, rs11546996, was associated to PNKP. In a previous GWAS, this SNP was associated with primary biliary cirrhosis although the causal gene was thought to be SPIB. Our methylation-adjusted method potentially adds new understanding to the genetic basis of complex diseases that disproportionally affect African Americans.