DNA Methylation-Regulated ZDHHC24 Exacerbates the Risk of Intracranial Aneurysms

Area of Science:

• Genetics and Molecular Biology
• Cardiovascular Research
• Neuroscience

Background:

• Palmitoylation is crucial for endothelial cell (EC) functions like angiogenesis and migration.
• The role of palmitoylation in intracranial aneurysms (IAs) and the impact of DNA methylation on IA-related genes remain understudied.

Purpose of the Study:

• To investigate the causal links between palmitoylation-related genes, DNA methylation, and IA development.
• To elucidate the underlying molecular mechanisms contributing to IA pathogenesis.

Main Methods:

• Employed Mendelian randomization (MR) methods, including two-sample MR and summary-data-based MR (SMR).
• Utilized mediation analysis and sensitivity analyses to validate findings.
• Conducted transcriptomic analysis to assess gene expression differences.

Main Results:

• ZDHHC24 gene overexpression showed a significant positive correlation with increased IA risk (21.85% increase per SD increase in expression).
• Specific DNA methylation sites (cg01806972, cg10523820, cg18862171, cg26041493) were identified as mediators in the ZDHHC24-IA relationship.
• Transcriptomic analysis confirmed statistically significant differential expression of ZDHHC24 in IA pathogenesis (p < 0.001).

Conclusions:

• ZDHHC24 overexpression is causally associated with an elevated risk of intracranial aneurysms.
• Specific DNA methylation loci mediate the effect of ZDHHC24 on IA development.
• Findings highlight the importance of palmitoylation-related gene expression and DNA methylation in IA susceptibility.