Mediating factors in the association between educational attainment and stroke: A mendelian randomization study

Stroke is a common cardiovascular and cerebrovascular disease with high disability and mortality. Lower educational attainment has been reported to be associated with an increased risk of stroke, but it is unclear which pathways mediate this association.

Using genome-wide association studies (GWAS) based on European ancestry, we performed two-sample Mendelian randomization (MR) analyses to investigate the causal association of genetically estimated educational attainment with stroke and its subtypes. Then, we used mediation analyses to assess the extent to which seven cardiometabolic risk factors alone and in combination explain their effects.

Genetically estimated educational attainment was negatively associated with the risk of any stroke (AS), any ischemic stroke (AIS), ischemic stroke subtypes (large artery stroke [LAS], cardioembolic stroke [CES], and small vessel stroke [SVS]), and hemorrhagic stroke subtypes (cerebral hemorrhage [ICH] and subarachnoid hemorrhage [SAH]). For individual mediating effects, type 2 diabetes, hypertension, hyperlipidemia, and smoking mediated the impact of education on AS, AIS, and ischemic stroke subtypes, while obesity, NAFLD, and alcohol consumption played no role. For combined mediation, the proportion of the association that cardiometabolic mediators explained ranged from 4% (95% CI: 2.72%-5.27%) for SVS to 38.73% (95% CI: 37.42%-40.05%) for LAS. Nevertheless, they did not account for any of the estimates for hemorrhagic stroke subtypes.

Higher educational attainment would have a protective effect on stroke and its subtypes, and cardiometabolic risk factors mediated part proportion of this association. Hence, patients with low education should pay more attention to managing cardiometabolic diseases to prevent stroke.