Exploring the causal effect of genetically predicted blood and cerebrospinal fluid metabolites and metabolic pathways on intracranial aneurysm.

ObjectivePrevious studies have identified significant alterations in metabolites in patients with intracranial aneurysm. This study aimed to evaluate the causal relationships of metabolites in both blood and cerebrospinal fluid with intracranial aneurysm at the genetic level using bidirectional Mendelian randomization analysis.MethodsGenetic instrumental variables for 1400 blood metabolites were obtained from a genome-wide association study analysis involving 8299 individuals, while 338 cerebrospinal fluid metabolites were sourced from another genome-wide association study involving 291 individuals. Outcome data for intracranial aneurysm were retrieved from the International Stroke Genetics Consortium, and validation data were retrieved from the FinnGen study. The primary analysis employed the inverse-variance weighted method, supported by sensitivity analysis to address pleiotropy and enhance robustness. Replication analysis and meta-analysis were performed to enhance the robustness of the findings. Colocalization analysis was used to assess the potential shared genetic architecture between metabolites and intracranial aneurysm, and metabolic pathway analysis was performed using MetaboAnalyst 6.0.ResultsFollowing false discovery rate correction, four and five genetically predicted blood metabolites showed inversely causal associations with intracranial aneurysms and subarachnoid hemorrhage, respectively, in the discovery group, while no cerebrospinal fluid metabolites showed significant causal associations with three intracranial aneurysm phenotypes. After performing a meta-analysis incorporating the results from the replication data, we identified 1-arachidonoyl-GPC (20:4n6) (odds ratio: 0.90) and 1-palmitoyl-2-arachidonoyl-GPC (16:0/20:4n6) (odds ratio: 0.92) as potential protective factors against intracranial aneurysms as well as (N(1) + N(8))-acetylspermidine (odds ratio: 0.83) as a potential protective factor against subarachnoid hemorrhage.ConclusionsOur findings establish a potential causal link between blood/cerebrospinal fluid metabolites and intracranial aneurysm. Furthermore, the identified metabolites and pathways provide valuable insights into the pathogenic mechanisms and progression of intracranial aneurysm.