The Role of Common and Rare Genetic Variation in Subtypes of Epilepsy
Creators: name: Campbell, Ciaran
Publisher: name: Royal College of Surgeons in Ireland
Year: 2022
Subjects: subject: 60408 Genomics
subject: FOS: Biological sciences
subject: 110903 Central Nervous System
subject: FOS: Clinical medicine
subject: 110904 Neurology and Neuromuscular Diseases

description: Epilepsy is a neurological condition affecting roughly 60 million people worldwide and40,000 people in Ireland. Epilepsy has a range of aetiologies, dependant on subtype, ranging from complex and multifactorial to monogenic. The research in this thesis is an exploration of the role of genetic variation in various types of epilepsy. First, I present the largest genome-wide association study (GWAS) of epilepsy to date derived from data on over 29,000 cases of epilepsy obtained from clinical settings and52,538 controls. This GWAS identified 22 significant loci associated with ‘genetic generalised epilepsy’, and none with ‘focal epilepsy’. This GWAS was meta-analysed with data on over21,000 epilepsy cases and 1 million population controls obtained from biobanks. Meta-analysing the primary and biobank GWAS revealed an additional 8 loci associated with epilepsy. Heritability analysis revealed that genetic generalised epilepsy has the highest SNP-based heritability estimate of any disease, and the third highest SNP-based heritability estimate compared to the traits body mass index (BMI) and height. I then present research into the genetic basis of the developmental and epileptic encephalopathies (DEEs). The DEEs are severe, childhood-onset epilepsies which occur in instances with no family history of epilepsy and co-present with intellectual disability. Given their severe, early-onset phenotype the DEEs have traditionally been presumed to be monogenic disorders. Using a method known as polygenic risk scoring (PRS) I show that the DEEs have an increased common genetic burden for epilepsy, relative to controls. I also show that this increased PRS burden is present in DEE cases both with and without an identifiable, likely deleterious rare genetic variant. This increased polygenic burden directly challenges the assumption that DEEs are purely monogenic disorders. People with epilepsy are at an increased risk for a variety of psychiatric disorders, relative to the general population, with one in three people with epilepsy experiencing some sort of psychiatric illness over the course of their lifetime. I explored the role of PRS for psychiatric illnesses in people with epilepsy. Using data from the UK Biobank on over 7,000 epilepsy samples, I showed that people with epilepsy have an increased polygenic burden for schizophrenia, depression, and attention deficit hyperactivity disorder (ADHD), relative to population controls. Meta-analyses of these data with epilepsy samples from the EpiPGX consortium found a further enrichment of PRS for schizophrenia and depression in people with drug-resistant epilepsy, who are most at risk of psychiatric illness. Levetiracetam (LEV) is a commonly prescribed, effective, anti-seizure medicine. Psychiatric side-effects effect roughly 20% of epilepsy patients taking LEV, with roughly 1% experiencing acute psychosis. We found that people with epilepsy who experience LEV-induced psychosis had an enrichment of PRS for schizophrenia, relative to epilepsy patients who experience no psychiatric side-effects to LEV-treatment. Rare-variant analysis found no evidence of an increased burden of rare genetic variants in people who experience LEV-induced psychosis. Finally, I present research into the genetic basis of drug-resistant epilepsy. Roughly 30% of people with epilepsy will continue to have seizures after treatment with an appropriate anti-seizure medicine (ASM). I investigated whether the response to individual ASMs was associated with common genetic variation. GWAS were conducted on responders to specific ASMs or groups of functionally related ASMs, using non-responders as controls did not find any significant loci associated with ASM response, nor did PRS analyses based on risk variants for epilepsy and neuropsychiatric disorders, and ASM resistance itself. The research presented in this thesis mark various important contributions to our understand of the genetics of epilepsy.