Promising Therapeutic Targets for Intracranial Aneurysms: A Systematic Druggable Genome-Wide Mendelian Randomization

Area of Science:

• Genetics
• Pharmacology
• Neurology

Background:

• Intracranial aneurysm (IA) is a dangerous dilation of cerebral arteries with high mortality.
• Current treatments and early diagnosis have improved, but effective disease-modifying therapies for IA are lacking.
• Understanding IA pathophysiology is crucial for developing targeted treatments.

Purpose of the Study:

• To identify potential pharmaceutical targets for preventing and treating intracranial aneurysms (IA).
• To utilize a Mendelian randomization (MR) approach to investigate causal relationships between druggable genes and IA risk.

Main Methods:

• Identified genetic variants for 1,577 druggable genes using expression and methylation data.
• Conducted a large-scale genome-wide association study (GWAS) meta-analysis for IA (10,754 cases, 306,882 controls).
• Performed MR analysis and validated results with sensitivity analyses (HEIDI, Bayesian colocalization).

Main Results:

• Elevated SLC22A5 and SLC22A4 expression linked to increased IA and subarachnoid hemorrhage (SAH) risk.
• Increased NT5C2 expression associated with reduced IA and SAH risk.
• HTRA1 protein expression and CHRNA3 methylation correlated with higher IA and SAH risk.

Conclusions:

• Identified four druggable target genes associated with IA and SAH through large-scale MR analysis.
• Highlighted HTRA1 as a potential protein target for medical intervention in IA.
• SLCC22A5, SLC22A4, NT5C2, and CHRNA3 represent potential therapeutic targets for IA.