Unraveling the causal association of epigenetic age acceleration with common oral diseases and its underlying mechanisms: findings from Mendelian randomization and integrative genetic analysis.

<h4>Objective</h4>The epigenetic clock(definition) is recognized as a highly accurate predictor of biological aging, but the relationship between epigenetic age acceleration and oral diseases remains poorly understood. This study aimed to investigate the causal associations between epigenetic age acceleration and oral diseases and identify the shared gene expressions.<h4>Methods</h4>A two-phase study design was used: in phase 1, we conducted MR analysis to investigate the association between epigenetic age acceleration and common oral diseases. In phase 2, we conducted transcriptome-wide association studies (TWAS) to identify gene expressions linked to phenotypes with positive outcomes. Subsequently, we performed summary-based MR (SMR) analyses integrating expression quantitative trait loci (eQTL) datasets to ascertain whether these gene expressions could affect the phenotypes. Finally, we performed biological pathway enrichment analysis to investigate the potential mechanisms.<h4>Results</h4>MR analysis revealed significant causal relationships between epigenetic age acceleration and oral diseases. Specifically, GrimAge was associated with an increased risk of periodontitis (OR = 1.160, 95% CI 1.010-1.333, p = 0.036 in FinnGen cohort; OR = 1.120, 95% CI 1.000-1.255, p = 0.049 in GLIDE consortium). PhenoAge showed a significant association with stomatitis (OR = 1.062, 95% CI 1.007-1.120, p = 0.026). Intrinsic epigenetic age acceleration (IEAA) was linked to a higher risk of oral lichen ruber planus (OR = 1.128, 95% CI 1.036-1.230, p = 0.006). Reverse MR analysis identified a bidirectional causal relationship between oral lichen ruber planus and IEAA (OR = 1.127, 95% CI 1.006-1.263, p = 0.039). No significant associations were observed between epigenetic age acceleration and dental caries, recurrent aphthous ulcers, or oral leukoplakia (all p > 0.05). Sensitivity analyses confirmed the robustness of these findings. TWAS and SMR identified eight genes associated with the effect of GrimAge on periodontitis, six genes associated with the effect of PhenoAge on stomatitis, four genes associated with the effect of IEAA on oral lichen ruber planus and seven genes associated with the effect of lichen ruber planus on IEAA.<h4>Conclusions</h4>This study revealed causal relationships between epigenetic age acceleration and common oral diseases, and explored the relevant mechanisms, highlighting the potential novel strategies for prevention.