Causality of genetically determined metabolites and metabolic pathways on stroke: a two-sample mendelian randomization study

Abstract Background Stroke is the second leading cause of death worldwide. While extensive research has been conducted on stroke risk factors, the underlying biological mechanism remains not fully understood. This study aims to investigate the causal effect of circulation metabolites on stroke risk. Methods A two-sample Mendelian Randomization (MR) analysis was conducted to assess the causality of circulation metabolites on stroke. A genome-wide association study (GWAS) of 486 metabolites served as the exposure, with 5 different stroke phenotypes as outcomes, including ischemic stroke with cardioembolic, ischemic stroke with large artery atherosclerosis, ischemic stroke, small vessel ischemic stroke, and lacunar stroke. Causal estimates were calculated using Inverse-variance weighted (IVW) method, with sensitivity analyses using methods such as weight mode, weight median, MR-egger, and simple mode. Metabolic pathway analysis was performed using the web-based metaboanalyst 6.0. All statistical analyses were conducted in R software. Results The MR analysis revealed a total of 82 causative associations between metabolites and different stroke phenotypes. 14 significant metabolic pathways were identified, with the arachidonic acid metabolic pathway showing correlation with stroke of multiple phenotypes. Conclusion The findings suggest that the identified metabolites and metabolic pathways could serve as useful circulating metabolic biomarkers for stroke screening and prevention in clinical practice. They may also be considered as candidate molecules for future exploration of mechanisms and selection of drug targets.