Genetic evidence for the causal relationship between cerebrospinal fluid metabolites and intracranial aneurysms: a bidirectional two-sample Mendelian randomization study

Intracranial Aneurysms (IA) are life-threatening cerebrovascular diseases, and their pathogenesis remains not fully understood. This study aims to systematically evaluate the causal relationship between cerebrospinal fluid (CSF) metabolites and IA through bidirectional two-sample Mendelian randomization (MR) analysis to identify potential biomarkers and therapeutic targets. Using genome-wide association study data from public databases, the primary analysis was conducted with inverse variance weighting, supplemented by MR-Egger regression, weighted median, weighted mode, and simple mode. Sensitivity analyses were performed using heterogeneity tests, horizontal pleiotropy tests, and leave-one-out analyses to ensure the stability of the results. Forward MR analysis revealed that 1-arachidonoyl-gpc (20:4n6), 2’-deoxyuridine, 3-hydroxystachydrine, 5-hydroxyhexanoate, isobutyrylcarnitine (C4), phenylacetylglutamine, and X-10457 were protective factors for IA. In contrast, 2-hydroxybutyrate/2-hydroxyisobutyrate, arabonate/xylonate, argininosuccinate, citrate, cysteinylglycine disulfide, and isovalerate were identified as risk factors for IA. Reverse MR analysis showed a significant causal relationship between IA and changes in the concentrations of 14 CSF metabolites. Sensitivity analyses indicated the robustness of these findings. This study, through bidirectional MR analysis, uncovered the causal relationship between CSF metabolites and IA, highlighting the significant roles of various amino acids and lipid metabolites in the pathophysiology of IA. These metabolites not only provide new insights into the mechanisms underlying IA but also present potential biomarkers and therapeutic targets, offering theoretical support for early intervention and prevention strategies for the disease. This study aimed to systematically evaluate the causal relationship between cerebrospinal fluid (CSF) metabolites and intracranial aneurysms (IA) via bidirectional two - sample Mendelian randomization (MR) analysis, identifying potential biomarkers and therapeutic targets. Using public database GWAS data, the primary analysis used inverse variance weighting (IVW), supplemented by other methods. Heterogeneity, horizontal pleiotropy, and leave - one - out analyses were conducted for sensitivity assessment. Forward MR found seven protective and six risk metabolites for IA. Reverse MR showed a significant causal link between IA and 14 CSF metabolite concentration changes, with sensitivity analyses validating the results. Bidirectional MR uncovered the causal relationship between CSF metabolites and IA, highlighting metabolite roles. These offer new insights into IA mechanisms, potential biomarkers, and therapeutic targets, providing theoretical support for early intervention and prevention.