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Promising Therapeutic Targets for Intracranial Aneurysms: A Systematic Druggable Genome-Wide Mendelian Randomization
Aierpati Maimaiti1, Lin Pan2, Yuxin Liu3
1Department of Neurosurgery, Xinjiang Medical University Affiliated First Hospital, Urumqi, China.
Insights
This study used Mendelian randomization to identify druggable genes for intracranial aneurysms (IA). Increased expression of SLC22A5/4 and HTRA1, and CHRNA3 methylation, raise IA risk, while NT5C2 offers protection.
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.
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 aimed 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 1,577 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 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 the HEIDI test and Bayesian colocalization.
Results:
Our study reveals that increased expression of SLC22A5 and SLC22A4 in the 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.
