Promising Therapeutic Targets for Intracranial Aneurysms: A Systematic druggable genome-wide Mendelian Randomization

Background:Intracranial aneurysm (IA), known as pathological dilation of cerebral arteries,commonly occurring at bifurcating arteries,carries a high risk of severe morbidity and mortality if left untreated.Although the treatment and early diagnosis have significantly improved,the complex pathophysiological process of IA formation presents significant challenges in the development of targeted therapies.Efficient disease-modifying therapies for IA are not yet available.This study aims to utilize the Mendelian randomization (MR) approach to identify potential pharmaceutical targets for preventing and treating IA. Methods:We systematically identified genetic variants associated with 1577 druggable genes utilizing gene expression, DNA methylation, and protein expression quantitative trait loci. Genome-wide association study (GWAS) summary statistics were derived from a meta-analysis concentrating on IA, encompassing 10,754 cases and 306,882 controls.Subsequently, we conducted a TwoSample MR analysis integrating the identified druggable genes to estimate the causal effects on IAs. The robustness of the MR results was additionally validated through sensitivity analyses employing diverse techniques, such as bidirectional MR analysis, Steiger filtering, and Bayesian colocalization. Results:Our study reveals that increased expression of SLC22A5 and SLC22A4 in blood is associated with higher risk of IA and subarachnoid hemorrhage (SAH), while higher expression of NT5C2 is linked to a reduced risk of IA and SAH. Methylation of SLC22A5 is positively correlated with IA prevalence, while NT5C2 methylation shows an inverse correlation. We also found that higher methylation of CHRNA3 is associated with increased IA prevalence. Additionally, increased blood protein expression of HTRA1 is associated with elevated risks of both IA and SAH,the bayesian colocalization analysis further supports the involvement of HTRA1 in both IA and SAH. Conclusion:This large-scale MR analysis pinpointed four druggable target genes associated with IA and SAH, also highlighting HTRA1 as a potential prior druggable protein for medical intervention of IA.