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Peer-reviewedCC BYAnnals of clinical and translational neurology

Disentangling the Genetic Relationship Between Sleep and Epilepsy.

  • Khang N Le1
  • Victoria E Jackson1,2
  • Rachel E Stirling3,4
  • Zachary F Gerring1,2
  • Remi Stevelink5
  • Samuel F Berkovic6,7
  • Ingrid E Scheffer6,7,8
  • Philippa J Karoly3,4
  • Melanie Bahlo1,2
  • Karen L Oliver1,6
8 affiliations
  1. 1The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
  2. 2Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
  3. 3Department of Biomedical Engineering, The University of Melbourne, Parkville, Victoria, Australia.
  4. 4Graeme Clark Institute of Biomedical Engineering, The University of Melbourne, Parkville, Victoria, Australia.
  5. 5Department of Child Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, European Reference Network EpiCARE, Utrecht, the Netherlands.
  6. 6Department of Medicine, Epilepsy Research Center, The University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.
  7. 7Bladin-Berkovic Comprehensive Epilepsy Program, Department of Neurology, Austin Health, Heidelberg, Victoria, Australia.
  8. 8The Florey Institute and Murdoch Children's Research Institute, Parkville, Victoria, Australia.
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{le2026disentangling,
  title = {{Disentangling the Genetic Relationship Between Sleep and Epilepsy.}},
  author = {Khang N Le and Victoria E Jackson and Rachel E Stirling and Zachary F Gerring and Remi Stevelink and Samuel F Berkovic and Ingrid E Scheffer and Philippa J Karoly and Melanie Bahlo and Karen L Oliver},
  journal = {Annals of clinical and translational neurology},
  year = {2026},
  month = nov,
  doi = {10.1002/acn3.70568},
  url = {https://europepmc.org/article/MED/42973051},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Disentangling the Genetic Relationship Between Sleep and Epilepsy.
AU  - Khang N Le
AU  - Victoria E Jackson
AU  - Rachel E Stirling
AU  - Zachary F Gerring
AU  - Remi Stevelink
AU  - Samuel F Berkovic
AU  - Ingrid E Scheffer
AU  - Philippa J Karoly
AU  - Melanie Bahlo
AU  - Karen L Oliver
PY  - 2026
DA  - 2026/11/02
JO  - Annals of clinical and translational neurology
DO  - 10.1002/acn3.70568
UR  - https://europepmc.org/article/MED/42973051
AB  - 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.
SN  - 2328-9503
ER  -