To investigate the causal relationship between white matter tracts (WMTs) changes ,altered functional networks  and epilepsy.

We obtained summary statistics from genome-wide association studies for 191 resting-state functional magnetic resonance imaging (rsfMRI) phenotypes and 105 WMTs phenotypes. The inverse variance weighted method (IVW) was employed to assess causal effects, while additional methods, such as MR-Egger, MR–RAPS, weighted mode, and weighted median, were included to examine heterogeneity, horizontal pleiotropy, and outliers.

We finally identified 10 rsfMRI phenotypes, 18 WMTs phenotypes causally associated with the risk of different types of epilepsy. For instance, the increase in the connectivity of visual, default mode, attention and limbic network, but decrease in the fractional anisotropy (FA) of fornix, was associated with lower risk of childhood absence epilepsy (CAE). The increased connectivity of motor network, together with the increased FA of corpus callosum external capsule，uncinate fasciculus, was associated with lower risk of juvenile myoclonic epilepsy (JME). The increase in the connectivity of visual, attention and default mode and central executive network, together with the increased posterior corona radiata FA was associated with lower risk of juvenile absence epilepsy (JAE). But anterior corona radiata, anterior limb of internal capsule and cingulum FA increased the risk of JAE.In addition, increased FA of posterior corona radiata and cingulum was associate with lower risk of focal epilepsy with hippocampal sclerosis (focal HS), however, increased FA in posterior thalamic radiation and uncinate fasciculus, together with increased connectivity in default mode and central executive network increased the risk of focal HS.

Our study supports the causal relationship between functional networks and WMTs in epilepsy, providing potential therapeutic targets for different subtypes of epilepsy.