Estimating in silico causal effects of DNA methylation on gene expression through genetic anchors in airway epithelium in asthma

Expression quantitative trait methylation (eQTM) analyses have identified numerous associations between DNA methylation (DNAm) and gene expression, but the causal pathways underlying such associations remain poorly understood. Using single-nucleotide polymorphisms (SNPs) as genetic anchors, we examined potential causal effects between DNAm and gene expression in cis and trans associations in nasal epithelial samples from youth with ( n = 219) and without ( n = 236) asthma. We conducted causal mediation analyses to assess whether DNAm affects gene expression or vice versa by using an adaptive bootstrap for the joint significance test to estimate causal effects for 38,562 eQTM pairs. DNAm is a plausible cause of gene expression in 73% of pairs. Genes in these eQTM pairs were significantly enriched in immune pathways and associated with asthma phenotypes. We replicated Expression Quantitative Trait Loci (eQTL) findings in various cell types in lung tissue and eQTL and Methylation Quantitative Trait Loci (meQTL) findings in the upper airway. These results suggest DNAm as a promising target for asthma prevention and therapy.