Decoding the immune-genetic basis of epigenetic clocks: evidence from single-cell transcriptome-wide Mendelian randomization and colocalization

Epigenetic clocks, serving as pivotal metrics for assessing biological aging, demonstrate significant associations with various disease risks and mortality. However, the immunocyte-specific regulatory mechanisms underpinning these associations remain largely elusive. We integrated single-cell cis-expression quantitative trait loci (cis-eQTLs) from the OneK1K cohort with two-sample Mendelian randomization and Bayesian colocalization to evaluate genetic associations between immune cell-specific gene expression and four DNA methylation-based epigenetic clocks. Lead associations were replicated using GTEx V11 (whole blood) and TenK10K (immune cell eQTL) datasets. Subsequent analyses, incorporating functional enrichment, protein-protein interaction networks, and a hierarchical target assessment framework, were employed to identify genes and pathways with therapeutic potential. We identified 22 significant eGene–immune cell genetic associations. Of these, 14 showed strong colocalization evidence (PPH4 ≥ 0.8) and 8 showed suggestive colocalization (0.5 < PPH4 <0.8). All 22 associations passed Steiger directionality filtering. Replication in GTEx V11 and TenK10K confirmed the direction of effect for the majority of lead associations, particularly ENO1, NDUFS5, ATM, and PPP1R17. Functional enrichment implicated DNA damage response, immune regulation, and metabolic pathways. PheWAS and druggability assessments prioritized genes with therapeutic potential. Our findings provide genetic evidence that immune cell gene expression influences epigenetic aging in a cell-type-specific manner and highlight candidate genes and pathways that may serve as potential targets for intervention in age-related diseases.