Causality Analysis Of Stroke And Epilepsy: A Two-Sample Bidirectional Mendelian Randomization Study

Background and purpose:Stroke and epilepsy are two common neurological diseases,which often co-exist in clinics and have a complex relationship.In the past,a large number of cohort studies and pathophysiological mechanism studies have concluded that stroke was one of the important causes of epilepsy,and proposed the concept of "post-stroke epilepsy".In recent years,some cohort studies have shown that epilepsy patients have a higher incidence of stroke than the general population.Therefore,the idea that epilepsy may be a cause of stroke has been raised,but it has not been supported by the study of pathophysiological mechanisms studies,and the causal relationship between epilepsy and stroke needs further study.In this study,genetic information of stroke and epilepsy was obtained from genome-wide association study(GWAS)database,and the causal relationship between stroke and epilepsy was investigated by two-sample bidirectional Mendelian Randomization(MR)research method.Methods:GWAS information of stroke(40,585 cases and 406,111 controls)and ischemic stroke(IS)(34,217 cases and 406,111 controls)were obtained from the MEGASTROKE consortium.And we also obtained the genetic information of IS subtypes,including 7,193 cases of cardioembolic stroke(CES)and 204,570 controls,4,373 cases of atherosclerotic stroke(LAS)and 146,392 controls and 5,386 cases of small-vessel stroke(SVS)and 192,662 controls.For the study,the genetic information of epilepsy(15,212 cases and 29,677controls),genetic generalized epilepsy(3,769 cases and 29,677 controls)and focal epilepsy(9,671 cases and 29,677 controls)were obtained from the GWAS of the International League Against Epilepsy(ILAE).The inverse variance weighted method(IVW)was used as the main analysis method,and the weighted median and MR-Egger as supplementary methods were used to test the reliability of IVW results.In addition,the Cochran’S Q test and leave-one analysis were used to test the heterogeneity and pleiotropy in this research process,which ensured the robustness of the results.Results:Results showed that stroke(OR:1.15,95% confidence interval(CI):1.05-1.27,P=0.004)and IS(OR: 1.13,95% CI: 1.04-1.22,P=0.004)were significantly related to the risk of epilepsy.CES(OR:1.04 95%CI:1.00-1.09,P=0.069)and LAS(OR: 1.04,95% CI: 0.97-1.10,P=0.273)did not show a clear causal relationship with epilepsy.The p value in SVS(OR:1.22,95% ci: 1.08-1.39,P=0.002)was less than 0.05.However,we considered that only one instrumental variable(IV)was obtained,and its pleiotropy and heterogeneity could not be tested by MR-Egger intercept and Cochran’S Q test.Therefore,this study concluded that CES had no significant correlation with the risk of epilepsy.Furthermore,in the reverse MR analysis,epilepsy(OR: 1.12,95% CI: 0.90-1.41,P=0.309),genetic generalized epilepsy(OR:1.07,95% CI: 0.98-1.16,P=0.149)and focal epilepsy(OR: 1.05,95% CI: 0.74-1.49,P=0.782)did not show a clear association with the incidence of stroke.Conclusion:The results of this MR study show that there is a clear causal effect of stroke and IS on epilepsy,which provides genetic support for the view that stroke is one of the causes of epilepsy.Besides,CES,LAS and SVS have no clear causal link to epilepsy.In the reverse causal inquiry,there is no clear causal relationship between epilepsy,including genetic generalized epilepsy and focal epilepsy,and stroke.The possible mechanism of the influence of epilepsy on the onset of stroke still needs further study.