Detecting Potential Mediators of the Causal Effect of Education Level on The Risk of Stroke: A Two-Step, Two-Sample Multivariable Mendelian Randomization Study

Abstract

Background: The effect of education level on the risk of stroke is not fully understood. The present study aimed to reveal the genetic and modifiable mediators for the effect of education level on the risk of stroke. Methods: Summary-level genetic data were obtained from GWAS consortia. Two-sample Mendelian Randomization (MR) analysis was performed to uncover the causal effect of education level on the risk of stroke, and regression-based multivariable MR (MVMR) analyses were used to explore potential mediators. Results: Genome-wide MR analyses showed that genetically determined higher education level was associated with reduced risk of stroke (Odds ratio (OR) per standard deviation (SD) increase: 0.74[95% confidence interval (CI): 0.58 to 0.94]; p = 0.013). We found instant coffee intake, never smoking status, body mass index (BMI), waist circumference (WC), waist-hip-ratio (WHR), Type-2 diabetes mellitus (T2DM), Diastolic pressure (DBP), Systolic pressure (SBP), Alanine aminotransferase (ALT), Platelet (PLT) and CTRP-1 (complement c1q tumor necrosis factor-related protein 1) had significant mediation roles in the effect of education level on the risk of stroke. The proportion of total effect mediated by these modifiable factors was 79%. Conclusion: We found many modifiable mediators had essential mediation roles in the effect of education level on the risk of stroke. Intervention on these mediators might have protective effect on the risk of stroke, which highlighted novel therapeutic targets.