Abstract
BACKGROUND: The causal association between educational attainment (EA) and stroke remains unclear. Hence, a novel multivariable Mendelian randomization (MVMR) approach was applied to solve this issue. METHODS: The single nucleotide polymorphisms (SNPs) from a recent genome-wide association study (GWAS) on years of schooling served as instruments. Univariable mendelian randomization (MR) and MVMR analyses were performed to detect the relationship between genetically predicted EA and the stroke risk. In the MVMR, cigarette consumption, alcohol consumption, body mass index (BMI), intelligence, and hypertension were adjusted. The summary statistics for stroke from the MEGASTROKE consortium included 446,696 participants (40,585 cases of stroke and 34,217 cases of ischemic stroke), most of whom were of European descent. RESULTS: In the univariable MR, genetically predicated EA could decrease the risks of total stroke (OR = 0.66, 95% CI 0.61-0.72, P = 2.70 × 10(-23)), ischemic stroke (OR = 0.67, 95% CI 0.61-0.73, P = 2.58 × 10(-18)), large artery atherosclerosis (OR = 0.51, 95% CI 0.40-0.64, P = 1.80 × 10(-8)), small vessel stroke (OR = 0.60, 95% CI 0.49-0.73, P = 5.59 × 10(-7)), and cardioembolic stroke (OR = 0.81, 95% CI 0.68-0.96, P = 1.46 × 10(-2)) using the inverse-variance weighted (IVW) estimator. Higher EA might be negatively correlated with the odds of total stroke (OR = 0.62, 95% CI 0.50-0.77, P = 1.44 × 10(-5)), ischemic stroke (OR = 0.63, 95% CI 0.50-0.80, P = 1.41 × 10(-4)), and cardioembolic stroke (OR = 0.59, 95% CI 0.39-0.90, P = 0.01), but was not significant in large artery atherosclerosis (OR = 0.65, 95% CI 0.37-1.15, P = 0.14) and small vessel stroke (OR = 0.68, 95% CI 0.41-1.13, P = 0.14) after controlling other exposures. CONCLUSIONS: We found that genetically predicated higher EA decreased the risks of total stroke, ischemic stroke, and cardioembolic stroke, independent of smoking, alcohol consumption, BMI, intelligence, and hypertension.