Causal Relationship between Ischemic Stroke and Malignant Brain Tumors: A Two-Sample Mendelian Randomization Analysis

Abstract

Object: Contemporary observational research has identified associations between cerebrovascular accidents, commonly referred to as strokes, and malignant cerebral neoplasms. However, these studies fall short of elucidating the presence of a direct causal relationship between the two conditions. In our investigation, we employ aggregated data derived from large-scale population-based genome-wide association studies (GWASs), to interrogate the potential causal linkages between these two pathologies. Method: This investigation leverages the two-sample Mendelian randomization (MR) methodology to elucidate the genetic underpinnings of the causal nexus between malignant cerebral neoplasms and ischemic cerebrovascular accidents. Rigorous quality control protocols were enacted to identify SNPs that exhibit a robust association with the exposure variable, namely malignant brain tumors. Analytical strategies, including MR-Egger regression, weighted median, inverse-variance weighted (IVW), simple mode, and weight mode methods, constituted the core of our MR analytical framework. Predominantly, the findings hinge upon the IVW method. To fortify the veracity of our conclusions, an array of sensitivity analyses such as MR-Egger regression, weighted median, MR pleiotropy, MR-PRESSO and radial MR, were deployed to meticulously evaluate heterogeneity and pleiotropy. Result: The findings derived from the IVW model reveal an absence of a significant causal nexus between malignant cerebral neoplasms and any categorization of cerebrovascular accidents, encompassing any strokes (AS) (OR 0.998, 95% CI 0.99-1.01, P=0.741), any ischemic strokes (AIS) (OR 0.999, 95% CI 0.99-1.01, P=0.999), large artery strokes (LAS) (OR 0.993, 95% CI 0.97-1.02, P=0.603), cardioembolic strokes (CES) (OR 1.012, 95% CI 0.99-1.03, P=0.275), and small vessel strokes (SVS) (OR 0.998, 95% CI 0.98-1.02, P=0.880) with respect to either an escalation or reduction in risk. Additionally, the analyses did not unveil any indications of heterogeneity or horizontal pleiotropy within the dataset. On a genome-wide scale, none of the variants associated with malignant brain tumors demonstrated relevance to the investigated outcomes. Conclusion: The outcomes of this MR investigation reveal the absence of a causal linkage between malignant cerebral neoplasms and ischemic cerebrovascular accidents. Nonetheless, the observed correlation between these two pathologies warrants attention, underscoring the necessity for heightened surveillance and care for individuals concurrently afflicted with both conditions.