Poster Presentation GENEMAPPERS 2026

Investigating the common polygenic risk contribution to seizure susceptibility in brain malformations of cortical development (#80)

Rebekah Harris 1 2 3 , Colin A Ellis 4 , Richard J Leventer 5 6 , Paul J Lockhart 5 , Greta Gillies 5 , Kate Pope 5 , Epi4K Consortium 7 , Ingrid E Scheffer 1 8 9 10 , Samuel F Berkovic 1 8 , Melanie Bahlo 2 3 , Karen L Oliver 1
  1. Department of Medicine (Austin Health), Epilepsy Research Centre, The University of Melbourne, Heidelberg, VIC, Australia
  2. Department of Medical Biology, The University of Melbourne, Parkville, VIC , Australia
  3. Genetics and Gene Regulation Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  4. Department of Neurology, University of Pennsylvania Perelman School of Medicine,, Pennsylvania, PA, USA
  5. Murdoch Children’s Research Institute, Parkville, VIC, Australia
  6. Department of Neurology, The Royal Children’s Hospital, Parkville, VIC, Australia
  7. Epi4K and Epilepsy Phenome Genome Project, .
  8. Bladin-Berkovic Comprehensive Epilepsy Program, Department of Neurology, Austin Health, Heidelberg, VIC, Australia
  9. Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia
  10. Murdoch Children’s Research Institute and Department of Paediatrics, University of Melbourne, Royal Children’s Hospital, Parkville, VIC, Australia

Malformations of cortical development (MCD) such as Polymicrogyria (PMG) and Periventricular Nodular Heterotopia (PVNH) have genetic and non-genetic causes. They commonly present with a spectrum of clinical features beyond their structural brain abnormalities. Around 70-80% of individuals with PMG and PVNH experience seizures1,2, yet the factors underlying variability in seizure susceptibility and severity are unclear. Common polygenic epilepsy risk background has recently been shown to modify the clinical expression of rare pathogenic variants in monogenic epilepsies3. Here, we assessed evidence for polygenic modification of MCDs by testing for common variant epilepsy risk enrichment in PMG and PVNH.

 

Patients with polymicrogyria or periventricular nodular heterotopia (PVNH) on brain magnetic  resonance imaging (MRI) were studied through the Epilepsy Phenome Genome Project4. All patients had epilepsy. Polygenic risk scores (PRS) were calculated for PMG (n=55), PVNH (n=49), and population controls (n=10,167) of European ancestry. PRS were generated with the PRS-CS-auto method5, using summary statistics from the largest all-epilepsy genome-wide association study (ILAE 2023)6. Statistical analyses used a fixed-effects regression model to account for sex and ancestry (top 10 principal components derived using PC-AiR).

 

PMG cases showed a nominally higher epilepsy PRS than population controls (mean 0.24 vs 0, OR = 1.30, P = 0.064). In contrast, epilepsy PRS did not differ in PVNH cases when compared to controls (mean -0.007 vs 0, P = 0.96).

 

These results suggest a modest enrichment of epilepsy-related polygenic risk in PMG that is not observed in PVNH, indicating potential differences in the genetic architecture underlying these MCDs. Common epilepsy-associated risk variants may contribute to the variable seizure expression seen in PMG. A replication analysis including >150 additional cases across three sites is underway, including cases with and without seizures to assess whether polygenic risk relates to cortical malformation itself or to seizure susceptibility.

  1. Leventer, R. et al. Clinical and imaging heterogeneity of polymicrogyria: a study of 328 patients. Brain : a journal of neurology 133 Pt 5, 1415–1427 (2010).
  2. Parrini, E. et al. Periventricular heterotopia: phenotypic heterogeneity and correlation with Filamin A mutations. Brain 129, 1892–1906 (2006).
  3. Oliver, K. L. et al. Investigating the effect of polygenic background on epilepsy phenotype in “monogenic” families. EBioMedicine 109, 105404 (2024).
  4. Shain, C. et al. Polymicrogyria-associated epilepsy: a multicenter phenotypic study from the Epilepsy Phenome/Genome Project. Epilepsia 54, 1368–1375 (2013).
  5. Ge, T., Chen, C.-Y., Ni, Y., Feng, Y.-C. A. & Smoller, J. W. Polygenic prediction via Bayesian regression and continuous shrinkage priors. Nat. Commun. 10, 1776 (2019).
  6. International League Against Epilepsy Consortium on Complex Epilepsies. GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture. Nat. Genet. 55, 1471–1482 (2023).