Disentangling the Genetic Relationship Between Sleep and Epilepsy

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.

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.

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.

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.