Causal relationship between mitochondrial-associated proteins and cerebral aneurysms: a Mendelian randomization study

Area of Science:

• Genetics and Genomics
• Neurology
• Biochemistry

Background:

• Cerebral aneurysms are dangerous cerebrovascular conditions with poor outcomes.
• Multiple factors contribute to cerebral aneurysm development.
• Mitochondrial dysfunction is increasingly recognized in various diseases.

Purpose of the Study:

• To investigate the causal association between mitochondrial-associated proteins and the risk of cerebral aneurysms.
• To identify specific mitochondrial proteins that may serve as risk factors or therapeutic targets for cerebral aneurysms.

Main Methods:

• Utilized Mendelian randomization (MR) analysis with large-scale GWAS summary statistics.
• Employed various MR methods (MR-Egger, weighted mode, IVW, etc.) to assess causal relationships.
• Conducted sensitivity analyses to evaluate heterogeneity and pleiotropy, and reverse MR to check for reverse causality.

Main Results:

• Identified six mitochondrial proteins associated with increased risk of subarachnoid hemorrhage (aSAH), including CCDC90B, tRNA PusA, and AIF1 (all with FDR q < 0.1).
• CCDC90B, tRNA PusA, and MRM3 showed associations with unruptured intracranial aneurysms (uIA).
• TIM14 demonstrated a potential causal relationship with aSAH, and sensitivity analyses confirmed robustness.

Conclusions:

• Confirmed a causal link between specific mitochondrial-associated proteins and cerebral aneurysm risk.
• Suggests CCDC90B, tRNA PusA, and MRM3 as potential common risk factors for both ruptured and unruptured aneurysms.
• Highlights AIF1 and NAGS for aSAH risk, and TIM14 for potential interaction with aSAH, paving the way for targeted research.