Abstracts

Rationale: The epilepsies have a range of aetiologies ranging from monogenic to multifactorial. More common forms of epilepsy have a complex genetic architecture with a substantial missing heritability component. Previous genome-wide association studies (GWAS) coordinated by the ILAE have identified 16 genetic loci associated with common forms of epilepsy. These loci include genes known to harbour mutations that cause rare epileptic encephalopathies and identified candidate loci with potential for drug repurposing. Here we present an update to the ILAE epilepsy GWAS meta-analysis, featuring a larger sample cohort that includes data from the ongoing Epi25 Collaborative project.

Methods: We performed GWAS meta-analysis of previously published results from the ILAE complex genetics consortium (15,000 cases), and newly available data, including over 11,000 cases from the Epi25 project. We analysed three broad epilepsy subtypes: ‘genetic generalised epilepsy’ (GGE), ‘focal epilepsy,’ and ‘all epilepsy.’ Post-association, the resultant summary statistics were incorporated into gene expression enrichment analysis, heritability analyses, and screened for potential drug repurposing targets.

Results: Meta-analysis identified new genetic loci associated with epilepsy. We identified 6 genome-wide significant loci associated with ‘all epilepsy,’ and 22 loci associated with ‘GGE.’ The significant loci include replications of nearly all previously identified epilepsy GWAS signals. Gene enrichment analysis found a significant enrichment of genes expressed in the brain, in particular during the mid-prenatal phase of brain development. We identified new targets for potential drug repurposing.

Conclusions: The results presented here are the largest epilepsy GWAS to date and have identified novel genetic loci associated with epilepsy, furthering our understanding of the aetiology of the complex epilepsies. The development of larger, more highly-powered epilepsy GWAS will allow for further research into the genetics of epilepsy using techniques such as polygenic risk scoring and mendelian randomisation.

Funding: Please list any funding that was received in support of this abstract.: This project was funded by the International League Against Epilepsy.