Using eQTL Mendelian randomization and transcriptomic analysis to identify the relationship between ion channel genes and intracranial aneurysmal subarachnoid hemorrhage

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Aneurysmal subarachnoid hemorrhage (aSAH) is a complex condition associated with high disability and mortality rates, leading to poor clinical outcomes. Previous observational studies have suggested a link between ion channel genes and aSAH, but the causal relationship remains uncertain. This study utilized Mendelian randomization (MR) to explore the causal association between ion channel genes and aSAH, employing 5 MR methods: inverse variance weighted (IVW), MR-Egger, maximum likelihood, weighted median, and weighted mode. If results from these methods are inconclusive, IVW will be prioritized as the primary outcome. Additionally, MR-Egger, MR-PRESSO, and Cochrane Q tests were conducted to assess heterogeneity and pleiotropy. The stability of MR findings was evaluated using the leave-one-out approach; Bonferroni correction tested the strength of the causal relationship between exposure and outcome. The MR analysis revealed that CACNA2D3 was positively correlated with aSAH (OR 1.245; 95% confidence intervals [CI] 1.008-1.537; P = .042), while ANO6 showed a negative correlation (OR 0.728; 95% CI 0.533-0.993; P = .045). Our findings indicate that increased expression of CACNA2D3 promotes aSAH whereas elevated levels of ANO6 inhibit it. Transcriptome data from intracranial aneurysm samples confirmed significant differential expression of CACNA2D3 and ANO6 between ruptured and unruptured groups. CACNA2D3 being higher in ruptured cases while ANO6 was more expressed in unruptured ones. Furthermore, GeneMANIA analysis along with functional enrichment provided insights into risk factors for aSAH. Through MR analysis, we established a causal link between ion channel genes and aSAH, which helps to better understand the pathogenesis of aSAH and provide new therapeutic targets.

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