A genetic association study has identified 22 significant relationships linking immune cell-specific gene expression to epigenetic clocks used to assess biological aging. Reporting in Epigenetics & Chromatin, researchers evaluated how gene regulation within specific immune cell types relates to four DNA methylation-based measures of biological aging, addressing regulatory mechanisms that connect epigenetic aging metrics with disease risks and mortality.
To investigate these connections, the investigators integrated single-cell cis-expression quantitative trait loci from the OneK1K cohort with two-sample Mendelian randomization and Bayesian colocalization analyses.
The analysis identified 22 significant eGene–immune cell genetic associations across the investigated cell types. Among these 22 associations, 14 exhibited strong Bayesian colocalization evidence with posterior probabilities of hypothesis four (PPH4) equal to or exceeding 0.8, while the remaining 8 showed suggestive colocalization with PPH4 values between 0.5 and 0.8.
The researchers replicated their lead findings using whole blood data from the GTEx V11 dataset and immune cell expression quantitative trait loci from the TenK10K cohort. These replication analyses confirmed the direction of effect for the majority of the lead associations, with particular confirmation observed for the genes ENO1, NDUFS5, ATM, and PPP1R17.
Subsequent functional enrichment analyses implicated the DNA damage response, immune regulation, and metabolic pathways in these epigenetic aging associations. By incorporating protein-protein interaction networks alongside phenome-wide association studies and druggability assessments within a hierarchical target assessment framework, the study prioritized candidate genes with therapeutic potential, providing genetic evidence that immune cell gene expression influences epigenetic aging in a cell-type-specific manner.
The study addresses an area of aging biology where the immunocyte-specific regulatory mechanisms underpinning associations between biological aging metrics, disease risks, and mortality have remained largely elusive.
Beyond identifying genetic links, the analytical workflow focused on identifying genes and biological pathways with therapeutic potential.
The peer-reviewed, accepted research has been released early to provide faster access ahead of the final Version of Record, carrying a permanent digital object identifier while remaining subject to further edits.
Subject of Research: Genetic associations between immune cell gene expression and epigenetic clocks
Article Title: Decoding the immune-genetic basis of epigenetic clocks: evidence from single-cell transcriptome-wide Mendelian randomization and colocalization
Article References: Sun, D., Mo, X., Zou, S., Zou, J., & Zhao, Z. (2026). Decoding the immune-genetic basis of epigenetic clocks: evidence from single-cell transcriptome-wide Mendelian randomization and colocalization. Epigenetics & Chromatin. https://doi.org/10.1186/s13072-026-00711-z
Image Credits: AI Generated
DOI: 10.1186/s13072-026-00711-z
Keywords: epigenetic clocks, biological aging, Mendelian randomization, Bayesian colocalization, immune cells, cis-eQTL, gene expression, DNA methylation, Decoding, immune-genetic, basis, epigenetic
News Source: Juliet Wilcox. (November 7, 2026). Genetic Study Links Immune Cell Gene Expression to Epigenetic Aging Clocks. Scienmag.
