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Causal relationship between mitochondrial-associated proteins and cerebral aneurysms: a Mendelian randomization study
Shuai Wang1, Jiajun Wang1, Zihui Niu1
1Department of Neurosurgery, The Affiliated Chuzhou Hospital of Anhui Medical University, The First People's Hospital of Chuzhou, Chuzhou, Anhui, China.
Background:
Cerebral aneurysm is a high-risk cerebrovascular disease with a poor prognosis, potentially linked to multiple factors. This study aims to explore the association between mitochondrial-associated proteins and the risk of cerebral aneurysms using Mendelian randomization (MR) methods.
Methods:
We used GWAS summary statistics from the IEU Open GWAS project for mitochondrial-associated proteins and from the Finnish database for cerebral aneurysms (uIA, aSAH). The association between mitochondrial-associated exposures and cerebral aneurysms was evaluated using MR-Egger, weighted mode, IVW, simple mode and weighted median methods. Reverse MR assessed reverse causal relationship, while sensitivity analyses examined heterogeneity and pleiotropy in the instrumental variables. Significant causal relationship with cerebral aneurysms were confirmed using FDR correction.
Results:
Through MR analysis, we identified six mitochondrial proteins associated with an increased risk of aSAH: AIF1 (OR: 1.394, 95% CI: 1.109-1.752, p = 0.0044), CCDC90B (OR: 1.318, 95% CI: 1.132-1.535, p = 0.0004), TIM14 (OR: 1.272, 95% CI: 1.041-1.553, p = 0.0186), NAGS (OR: 1.219, 95% CI: 1.008-1.475, p = 0.041), tRNA PusA (OR: 1.311, 95% CI: 1.096-1.569, p = 0.003), and MRM3 (OR: 1.097, 95% CI: 1.016-1.185, p = 0.0175). Among these, CCDC90B, tRNA PusA, and AIF1 demonstrated a significant causal relationship with an increased risk of aSAH (FDR q < 0.1). Three mitochondrial proteins were associated with an increased risk of uIA: CCDC90B (OR: 1.309, 95% CI: 1.05-1.632, p = 0.0165), tRNA PusA (OR: 1.306, 95% CI: 1.007-1.694, p = 0.0438), and MRM3 (OR: 1.13, 95% CI: 1.012-1.263, p = 0.0303). In the reverse MR study, only one mitochondrial protein, TIM14 (OR: 1.087, 95% CI: 1.004-1.177, p = 0.04), showed a causal relationship with aSAH. Sensitivity analysis did not reveal heterogeneity or pleiotropy. The results suggest that CCDC90B, tRNA PusA, and MRM3 may be common risk factors for cerebral aneurysms (ruptured and unruptured), while AIF1 and NAGS are specifically associated with an increased risk of aSAH, unrelated to uIA. TIM14 may interact with aSAH.
Conclusion:
Our findings confirm a causal relationship between mitochondrial-associated proteins and cerebral aneurysms, offering new insights for future research into the pathogenesis and treatment of this condition.
Insights
This study used Mendelian randomization to link mitochondrial proteins to cerebral aneurysms. Several proteins, including CCDC90B and tRNA PusA, were found to increase the risk of both ruptured and unruptured cerebral aneurysms.
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.
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