Age-related hearing impairment (ARHI) is a major planetary health burden that is in need of precision medicine for prevention, diagnosis, and treatment. The present study was set out to identify candidate epigenetic markers for ARHI. Associations of genetically predicted DNA methylation levels with ARHI risk were evaluated using two sets of blood DNA methylation genetic prediction models in 147,997 cases and 575,269 controls of European descent. A total of 1314 CpG sites (CpGs) were significantly associated with ARHI risk at a false discovery rate (FDR) <0.05, including 12 putatively causal CpGs based on fine-mapping analysis. Measured methylation levels of 247 of the associated CpGs were significantly correlated with measured expression levels of 127 nearby genes in blood at an FDR <0.05. A total of 37 CpGs and their 18 nearby genes showed consistent association directions for the methylation-gene expression-ARHI risk pathway. Importantly, three genes (PEX6, TCF19, and SPTBN1) were enriched in auditory disease categories. Our results indicate that specific CpGs may modulate ARHI risk by regulating the expression of candidate ARHI target genes. Future precision medicine and biomarker development research on ARHI are called for.
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