Polygenic Risk of Epilepsy and Post-Stroke Epilepsy

Background and Aims Epilepsy 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). Methods We 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. Results Among 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]). Conclusions Our 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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Dr. de Havenon has received investigator-initiated clinical research funding from the NIH, consultant fees from Novo Nordisk, royalty fees from UpToDate, and equity in TitinKM and Certus. JZ reports speaker honoraria for unbranded educational events from UCB and Eisai, royalties/writer honoraria from Liber AB, Neurologi i Sverige, Studentlitteratur AB, and Wiley; as an employee of Sahlgrenska University Hospital being principal investigator/sub-investigator in clinical trials sponsored by Bial, SK Life science, GW Pharma and UCB (no personal compensation). NKM is an editorial board member of the Neurology and convenor of the IPSERC. Dr. Mazumder was supported by the Fogarty International Center of the National Institutes of Health under Award Number K01TW012178. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The All of Us Research Program of the national Institutes of Health gave ethical approval for this work. The North West Centre for Research Ethics Committee gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes