Single-Cell Transcriptome-Wide Mendelian Randomization and Colocalization Analyses Uncover Cell-Specific Mechanisms...

Area of Science:

• Genomics
• Immunology
• Aging Research

Background:

• Epigenetic age acceleration (EAA) indicates biological aging beyond chronological age, linked to disease and death.
• The precise gene regulatory mechanisms driving epigenetic aging are not fully understood.

Purpose of the Study:

• To identify genes (eGenes) where cell-type-specific expression causally impacts major epigenetic clocks.
• To explore the role of immune-cell-specific gene regulation in biological aging.

Main Methods:

• Integration of single-cell expression quantitative trait loci (sc-eQTL) data across 14 immune cell types.
• Application of Mendelian randomization (MR) and Bayesian colocalization to infer causality.
• Phenome-wide association studies (PheWAS) to link eGenes with aging-related traits.

Main Results:

• Identified 58 unique eGenes with causal effects on epigenetic clocks (IEAA, HannumAge, GrimAge, PhenoAge).
• Key genes like ATM and DDX5 showed cell-type-specific effects, particularly in CD8 T and NK cells.
• Enrichment analysis linked eGenes to immune regulation, NF-κB signaling, and mitochondrial metabolism.
• PheWAS associated top eGenes (ATM, DDX5) with metabolic and immune disorders.

Conclusions:

• Immune-cell-specific gene regulation plays a critical role in biological aging.
• Identified candidate genes provide potential targets for future aging interventions.