DNA Methylation‐Regulated ZDHHC24 Exacerbates the Risk of Intracranial Aneurysms

PURPOSE: Recent studies have reported that palmitoylation plays a pivotal role in the process of angiogenesis, as well as in the motility and migration of endothelial cells (ECs). However, the role of palmitoylation in the pathogenesis of intracranial aneurysms (IAs) has not yet been systematically investigated. Moreover, alterations in DNA methylation and the expression of IA-related genes have not received sufficient attention. METHOD: The present study aims to employ Mendelian randomization (MR) methods to investigate the causal relationships and underlying mechanisms between palmitoylation-related genes, DNA methylation, and IAs. By employing two-sample MR analysis, summary-data-based Mendelian randomization (SMR) analysis, and mediation analysis, this study drew its conclusions. Furthermore, the robustness of these conclusions was evaluated through sensitivity analyses and transcriptomics approaches. FINDING: Our study revealed a significant positive correlation between the overexpression of the ZDHHC24 gene and increased risk of IA. For each one standard deviation increase in ZDHHC24 expression, the risk of IA increases by 21.85%. Further mediation effect analysis revealed that methylation sites cg01806972, cg10523820, cg18862171, and cg26041493 indirectly influence the occurrence of IA by regulating the expression of the ZDHHC24 gene, with mediation effects accounting for 33.19%, 26.71%, 32.93%, and 47.16% of the total effect, respectively. Sensitivity analysis provides evidence of the robustness of the research conclusion. The final transcriptomic analysis revealed a statistically significant differential expression of ZDHHC24 between experimental and control groups (p < 0.001), suggesting its potential involvement in IA pathogenesis. CONCLUSION: ZDHHC24 overexpression is causally linked to increased IA risk, and this relationship is mediated by specific DNA methylation loci. These findings underscore the roles of palmitoylation-related gene expression and DNA methylation in IA pathogenesis, offering novel insights into the molecular mechanisms underlying IA susceptibility.