Integrating epigenome-wide Mendelian randomization and multi-omics data validation to identify epigenetic drivers of idiopathic pulmonary fibrosis

While DNA methylation has been implicated in IPF pathogenesis, the tissue-specific causal effects of the epigenetic factors on IPF remain undetermined. Here, we performed epigenome-wide Mendelian randomization using blood-based methylation quantitative trait loci of 420,509 CpG sites and genome-wide association study for IPF to elucidate the causal effects of the CpG sites on IPF.

Totally, 452 CpG sites has shown putative causal effects on IPF risk after Bonferroni correction. Among them, 13 CpG sites have shown strong colocalization evidence with genetic factors associated with IPF. Specifically, DNA methylation at CpG sites within MAN2A2 and TRIM27 shows significant differences between IPF lungs and controls, correlating with altered mRNA expressions of these genes in lung tissues.