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.

Keywords: Druggable; Mendelian randomization; eQTL; intracranial aneurysm; pQTL; phenome‐wide.