Disentangling the Genetic Relationship Between Sleep and Epilepsy

OBJECTIVE: A bidirectional relationship between sleep and epilepsy is well recognised, yet the biological mechanisms linking them remain poorly understood. Both have a genetic basis, with genome-wide association studies (GWAS) capturing polygenic contributions. By leveraging GWAS summary statistics, we aimed to investigate their shared genetic architecture. METHODS: We analysed seven sleep traits (morningness chronotype, sleep duration, habitual short/long sleep, insomnia, daytime napping/sleepiness) with common epilepsy types (focal epilepsy and genetic generalised epilepsy [GGE]). For each trait pair, we estimated genome-wide genetic correlation, tested bidirectional causality, quantified polygenic overlap, performed gene-trait associations to identify putative pleiotropic genes, estimated local genetic correlations and investigated whether regions of significance were driven by shared causal variants using colocalisation and fine-mapping. RESULTS: Genome-wide analyses supported a positive genetic correlation between higher GGE risk and habitual short sleep, with extensive polygenic overlap (75%-97%) across seven sleep traits. Gene-trait analyses identified RMI1 as a putative sleep-epilepsy candidate, with 13 additional sleep-associated genes linked to monogenic epilepsies (e.g., KANSL1, GRIN2A). Locus-specific analyses identified 16 genomic loci of interest (13 sleep-GGE, 3 sleep-focal epilepsy). Morningness-GGE shared the largest number of locus-specific associations. No significant causal relationships were identified, and causal variants did not colocalise. INTERPRETATION: Our findings support complex shared genetic contributions between sleep and epilepsy, with distinct patterns for focal compared to generalised epilepsy. These differences may help explain syndrome-specific sleep-wake associations, including seizure timing and predisposition. By localising shared loci and highlighting specific overlapping genes, we provide a foundation for future research into the mechanisms underlying epilepsy-sleep comorbidities.