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Epilepsy is a heritable neurological disorder that is frequently comorbid with sleeping difficulties, including short/long sleep duration and insomnia. Although epidemiological studies have consistently reported the comorbidity between sleep disturbances and epilepsy, the shared genetic architecture and molecular mechanisms underlying this relationship remain poorly characterized, hindering therapeutic development. In this study, we integrated large-scale genome-wide association study (GWAS) summary statistics of European ancestry to dissect the genetic and molecular links between sleep traits and epilepsy. Using LDSC and GWAS-pw, we identified modest but statistically significant (Bonferroni-corrected) global and local genetic correlations between sleep behaviors and epilepsy. Subsequent CPASSOC cross-trait meta-analysis and transcriptome-wide association studies (TWAS) pinpointed specific pleiotropic loci and shared candidate genes, including SPAG7, VRK2, and LINC00925, which are functionally associated with neuroimmune signaling. While preliminary Phenome-Wide Association Study (PheWAS) profiling of these candidate targets did not identify major adverse associations in current databases, we emphasize that rigorous in vitro and in vivo experimental validations are required before considering them for therapeutic strategies. Finally, pleiotropy-robust bidirectional Mendelian Randomization (MR) analyses suggested unidirectional causal liability from epilepsy to short sleep duration. Although the estimated causal effect size was minimal, it reflects lifelong polygenic architecture rather than acute clinical magnitude. In conclusion, our multi-omics approach unveils the shared genetic architecture of the sleep-epilepsy axis and highlights potential biomarkers for future functional investigation.
Wang et al. (Fri,) studied this question.