Polygenic risk score analysis reveals shared genetic burden between epilepsy and psychiatric comorbidities

Background One in three people with epilepsy experiences psychiatric comorbidity, with higher rates in people with drug-resistant epilepsy. Despite their high heritabilities, finding genetic links between epilepsy and psychiatric disorders has proven difficult. We used polygenic risk scoring (PRS) to test whether people with epilepsy have an increased polygenic burden of common genetic variants for depression, anxiety, psychosis, and attention deficit/hyperactivity disorder (ADHD), and examined whether such polygenic burden influences the response to pharmacological treatment of epilepsy. Methods Phenotype data in the UK Biobank were assessed to identify people with 1) epilepsy (n=8 488), 2) depression (n=143 440), 3) psychosis (n=2 357), 4) ADHD (n=89), and 5) anxiety (n=18 222. Using genotype data and restricting to Caucasian-ancestry samples (n=409 634), PRS for each psychiatric trait were calculated and multinomial regression was used to compare 1) population controls, 2) people with epilepsy and no psychiatric illness, 3) people with epilepsy and the psychiatric trait of interest, and 4) people with the psychiatric trait of interest and no epilepsy. Fixed-effect meta-analysis was used to compare psychiatric PRS in drug-resistant and drug-responsive epilepsy samples from the UK Biobank (n=1 640) and the EpiPGX consortium (n=3 449). Results After correction for multiple testing, people with epilepsy showed elevated PRS for depression (p<2 x10−16), psychosis (p=0.04) and ADHD (p<0.001). Patients with drug-resistant epilepsy had an increased PRS for psychosis (p=0.002) and depression (p=0.0004) relative to responsive cases. Conclusion We present evidence that the common genetic basis of epilepsy overlaps with that of psychiatric conditions which are frequently comorbid in people with epilepsy. Common genetic variants that drive psychiatric illness are enriched in people with drug-resistant epilepsy. These results further our understanding of the genetic architecture of epilepsy and suggest a potential future role for polygenic interpretation of common variants in prognostic stratification, both for seizure-treatment outcomes and non-seizure comorbidities. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This research was funded in whole, or in part, by the Wellcome Trust [203914/Z/16/Z]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. This publication has emanated from research supported in part by a research grant from Science Foundation Ireland (SFI) under Grant Number 16/RC/3948 and co-funded under the European Regional Development Fund and by FutureNeuro industry partners This work is part of the European Unions Seventh Framework Programme (FP7/2007-2013) under grant agreement number 279062 (EpiPGX). We are grateful for support from the Epilepsy Society. This work was partly carried out at NIHR University College London Hospitals Biomedical Research Centre, which receives a proportion of funding from the UK Department of Healths NIHR Biomedical Research Centres funding scheme. ### 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 ethics committee of Beaumont Hospital, Dublin Ireland 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 All data produced are available online through an application to UK Biobank (https://www.ukbiobank.ac.uk/)