Multiomic Underpinnings of Drug Targets for Intracranial Aneurysm: Evidence From Diversified Mendelian Randomization

Abstract

Aims

The absence of pharmaceutics poses challenges in preventing intracranial aneurysm (IA) progression and rupture. This research emphasized identifying drug targets for IA through a druggable genome-wide Mendelian randomization (MR) analysis.

Methods

A two-sample MR analysis was performed leveraging cis-expression quantitative trait loci in the blood (n = 31,684) and arteries (n = 584) aligned with 5883 druggable genes as exposure and the largest IA summary statistics (n = 7495) as outcome. Bayesian colocalization analysis, plasma cis-protein quantitative trait loci (n = 35,559), and external IA cohorts (FinnGen, n = 2582; Zhou, n = 380) were used for validation. A phenome-wide MR (Phe-MR) incorporating 783 diseases uncovered side effects. Multivariable MR addressed unmeasured pleiotropy.

Results

Five druggable genes in blood and one in the coronary artery showed significant association with IA risk (p-_FDR ≤ 0.05). NT5C2, PRCP, and CRMP1 shared a common variant with IA (PPH4 ≥ 0.8). The external validation cohorts confirmed the effects of NT5C2 on IA (FinnGen cohort, Odds Ratio [OR], 0.81, 95% Confidential Interval [95% CI] 95% CI, 0.707–0.930; p = 0.003; Zhou cohort, OR, 0.68, 95% CI, 0.469–0.983; p = 0.041). The genetically predicted protein level of PRCP validated an inverse association with IA risk (OR, 0.734; 95% CI, 0.561–0.959; p = 0.023). The Phe-MR revealed insignificance for NT5C2 or PRCP. Direct causal effects on IA were 0.60 (95% CI, 0.457–0.797; p = 1.36E-05) for PRCP and 0.67 (95% CI, 0.527–0.860; p = 0.002) for NT5C2 after adjusting for IA modifiable risk factors.

Conclusions

NT5C2 and PRCP were identified as potential drug targets for IA, with effects independent of known modifiable risk factors. Targeting NT5C2 and PRCP appeared exclusively effective and safe.