We identified genetic instruments based on the meta-analyzed summary statistics from the stroke multi-ancestry genome wide association study [GCST005838 (67,162 cases and 454,450 controls)] and the International League Against Epilepsy Consortium on Complex Epilepsies [Generalized epilepsy: GCST007343 (n_case=3769, n_control=29677), Focal epilepsy: GCST007352 (n_case=9671, n_control=29677)]. We included the following epilepsy subtypes (only available for Caucasian patients): generalized epilepsy (GE), focal epilepsy (FE), childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), generalized epilepsy with tonic-clonic seizures (GTCS), focal epilepsy with hippocampal sclerosis (FHS), and focal lesion-negative epilepsy (FLNE). Analysis was restricted to independent variants. Variants of potential reverse causality were removed. For causal effect estimation we used the inverse-variance weighted estimate (IVW), MR-Egger, MR-RAPS, and MRPRESSO.

For the causal relationships between GE and stroke (GE-> stroke), stroke and GE (stroke-> GE), FE and stroke (FE->stroke), and stroke and FE (stroke->FE), the number of instruments were respectively 253, 213, 187, and 210. GE was associated with an increased risk of stroke [IVW, 95% confidence interval: 0.058 (0.028-0.088)], stroke was also associated with an increased risk of epilepsy [IVW: 0.059 (0.026-0.092)]. FE was associated with an increased risk of AS [IVW: 0.066 (0.029-0.102)]. Stroke was associated with an increased risk of focal epilepsy [IVW: 0.037(0.005-0.068)]. For epilepsy subtypes analyses, genetic predisposition to stroke was associated with an increased risk of JAE, CAE, FHS and FLNE. The reverse analysis shows no association of stroke with epilepsy subtypes.