Polygenic Risk of Epilepsy and Post-Stroke Epilepsy

Abstract

ABSTRACTBackground and AimsEpilepsy is highly heritable, with numerous known genetic risk loci. However, the genetic predisposition’s role in post-acute brain injury epilepsy remains understudied. This study assesses whether a higher genetic predisposition to epilepsy raises post-stroke or Transient Ischemic Attack (TIA) survivor’s risk of Post-Stroke Epilepsy (PSE).MethodsWe conducted a three-stage genetic analysis. First, we identified independent epilepsy-associated (p<5x10−8) genetic variants from public data. Second, we estimated PSE-specific variant weights in stroke/TIA survivors from the UK Biobank. Third, we tested for an association between a polygenic risk score (PRS) and PSE risk in stroke/TIA survivors from the All of Us Research Program. Primary analysis included all ancestries, while a secondary analysis was restricted to European ancestry only. A sensitivity analysis excluded TIA survivors. Association testing was conducted via multivariable logistic regression, adjusting for age, sex, and genetic ancestry.ResultsAmong 19,708 UK Biobank participants with stroke/TIA, 805 (4.1%) developed PSE. Likewise, among 12,251 All of Us participants with stroke/TIA, 394 (3.2%) developed PSE. After establishing PSE-specific weights for 39 epilepsy-linked genetic variants in the UK Biobank, the resultant PRS was associated with elevated odds of PSE development in All of Us (OR:1.16[1.02-1.32]). A similar result was obtained when restricting to participants of European ancestry (OR:1.23[1.02-1.49]) and when excluding participants with a TIA history (OR:1.18[1.02-1.38]).ConclusionsOur findings suggest that akin to other forms of epilepsy, genetic predisposition plays an essential role in PSE. Because the PSE data were sparse, our results should be interpreted cautiously.