Lightning Talk GENEMAPPERS 2026

Genetically predicted ketone bodies modify risk in severe childhood epilepsies (#12)

Khang N Le 1 , Karen L Oliver 1 2 , Bronwyn E Grinton 1 2 , Michael S Hildebrand 2 , Sam F Berkovic 2 3 , Ingrid E Scheffer 2 3 4 , Melanie Bahlo 1 5
  1. Genetics and Gene Regulation Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  2. Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, VIC, Australia
  3. Bladin-Berkovic Comprehensive Epilepsy Program, Department of Neurology, Austin Health, Heidelberg, VIC, Australia
  4. The Florey Institute and Murdoch Children’s Research Institute, Parkville, VIC, Australia
  5. Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia

Epilepsy is a common neurological disease that is clinically and genetically heterogeneous. Over 1000 single-gene causes are known [1], mostly associated with severe, early-onset childhood epilepsies, including those with a metabolic basis (e.g., GLUT-1 deficiency). The ketogenic diet, which elevates ketone bodies, can be an effective treatment for some epilepsy types. We investigated whether normal variation in genetically predicted metabolic background influences epilepsy risk using polygenic risk scores (PRSs). We hypothesised certain epilepsy syndromes would be more susceptible to specific metabolites, revealing sub-groups that may benefit from metabolic-targeted treatments.

We studied 429 patients with various forms of severe childhood epilepsies where SNP genotyping data was available for PRS calculation. PRSs were generated for 233 metabolites from the Karjalainen et al. (2024) GWAS [2] for all cases and 15,959 controls, using PRS-CS method [3]. Analyses were limited to European ancestry individuals. For each metabolite PRS, association between case versus control status was determined by logistic regression adjusted for sex and top ten ancestry principal components. Ketone body PRSs (PRS-Acetone, PRS-3-hydroxybutyrate) were further analysed by stratifying cases into seven epilepsy syndrome groups. P-values were Bonferroni corrected for multiple testing.

PRS-Acetone was nominally associated with reduced overall epilepsy risk (OR=0.87 [0.79-0.96], p-adjusted=0.062). In syndrome-stratified analyses, epilepsy with myoclonic-atonic seizures (EMAtS; n=51) demonstrated significantly protective association for both ketone bodies: PRS-Acetone (OR=0.70 [0.53-0.91], p-adjusted=0.018) and PRS-3-hydroxybutyrate (OR=0.68 [0.52-0.89], p-adjusted=0.01).

Our findings suggest that genetically predicted ketone body levels modify epilepsy risk, with strongest effects in EMAtS. These results highlight ketone body metabolism as potential therapeutic targets for specific epilepsy syndromes and aligns clinically with the ketogenic diet being an effective treatment for EMAtS [4]. Furthermore, it raises the possibility that ketone body PRSs may help explain the clinical variability observed between patients with regards to severity and treatment response.

  1. Oliver, K.L., et al., Genes4Epilepsy: An epilepsy gene resource. Epilepsia, 2023. 64(5): p. 1368-1375.
  2. Karjalainen, M.K., et al., Genome-wide characterization of circulating metabolic biomarkers. Nature, 2024. 628(8006): p. 130-138.
  3. Ge, T., et al., Polygenic prediction via Bayesian regression and continuous shrinkage priors. Nature Communications, 2019. 10(1): p. 1776.
  4. Stenger, E., et al., Efficacy of a ketogenic diet in resistant myoclono-astatic epilepsy: A French multicenter retrospective study. Epilepsy Res, 2017. 131: p. 64-69