机构:[1]Capital Med Univ, Xuanwu Hosp, Dept Neurosurg, Beijing, Peoples R China首都医科大学宣武医院[2]Capital Med Univ, Xuanwu Hosp, China Int Neurosci Inst China INI, Beijing, Peoples R China首都医科大学宣武医院
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.
基金:
The current research was supported by the Beijing Science and Technology Planning Project (Z231100004823013) and the National Natural
Science Foundation of China (82220108010).
第一作者机构:[1]Capital Med Univ, Xuanwu Hosp, Dept Neurosurg, Beijing, Peoples R China[2]Capital Med Univ, Xuanwu Hosp, China Int Neurosci Inst China INI, Beijing, Peoples R China
通讯作者:
通讯机构:[1]Capital Med Univ, Xuanwu Hosp, Dept Neurosurg, Beijing, Peoples R China[2]Capital Med Univ, Xuanwu Hosp, China Int Neurosci Inst China INI, Beijing, Peoples R China
推荐引用方式(GB/T 7714):
Fan Yu-Xiang,Lu Di,Yang Cheng-Bin,et al.Multiomic Underpinnings of Drug Targets for Intracranial Aneurysm: Evidence From Diversified Mendelian Randomization[J].CNS NEUROSCIENCE & THERAPEUTICS.2025,31(5):doi:10.1111/cns.70430.
APA:
Fan, Yu-Xiang,Lu, Di,Yang, Cheng-Bin,Song, Zi-Hao,Chen, Yi-Guang...&Zhang, Hong-Qi.(2025).Multiomic Underpinnings of Drug Targets for Intracranial Aneurysm: Evidence From Diversified Mendelian Randomization.CNS NEUROSCIENCE & THERAPEUTICS,31,(5)
MLA:
Fan, Yu-Xiang,et al."Multiomic Underpinnings of Drug Targets for Intracranial Aneurysm: Evidence From Diversified Mendelian Randomization".CNS NEUROSCIENCE & THERAPEUTICS 31..5(2025)