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

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.MethodsPhenotype 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).ResultsAfter correction for multiple testing, people with epilepsy showed elevated PRS for depression (p<2 x10−16), psychosis (p=0.04) and ADHD (p