부산대학교 도서관

Difficulties identifying drug-resistant epilepsy (DRE) at disease onset and complex temporal patterns of epilepsy represent challenges in research and clinical practice. A better understanding of the underlying mechanisms of DRE is needed to enable biomarker development, early diagnosis, and personalised treatments. This work explores the influence of genomic variation on DRE through genome-wide association (GWAS) and heritability analyses. It is part of a collaborative, European Commission funded project: EpiPGX (Epilepsy Pharmacogenomics: delivering biomarkers for clinical use). Individuals with epilepsy were recruited from specialised clinical centres across Europe. Healthy controls were obtained from several publically available sources. To establish whether common genomic variants are associated with DRE, two GWAS were performed by the Author. The first analysis, comparing individuals with DRE and controls with drug-responsive epilepsy, did not reveal any variants with genome-wide significance. The second analysis, comparing individuals with DRE and healthy controls, revealed several loci with genome-wide significance. The top genome-wide association signal (rs75700350), located at 4q31.1, likely represents an artefact. Other findings include the signals at loci 5p13.2, and 11p13, pointing to potentially significant candidate genes, SLC1A2 and SLC1A3, implicated in glutamate reuptake and excitotoxicity. Furthermore, one of these loci has been linked to an important epilepsy comorbidity, autism. The functional variants driving these signals may represent risk factors for drug resistance, epilepsy susceptibility, or variants affecting pathophysiological pathways common to DRE and its comorbidities. The main limitations of these GWAS analyses were small sample sizes and the lack of replication. To explore if drug resistance in epilepsy has a polygenic inheritance component, a single nucleotide polymorphism (SNP) heritability analysis was performed. This analysis yielded an estimate of DRE SNP heritability of 0.22, showing that drug resistance in epilepsy is heritable.