Genome-wide mapping of markers for epilepsy predisposition and treatment.

<p><strong>There is an increasing amount of evidence to suggest genetics plays a large role in governing an </strong><strong>individual's risk for developing epilepsy and their response to anti-epileptic drug treatment. Responses </strong><strong>can range from seizure control with first drug, complete resistance and serious idiopathic and doserelated </strong><strong>adverse events occurring upon exposure to specific drugs. This thesis consists of five studies </strong><strong>with a common aim of identifying novel genetic influences on epilepsy predisposition and treatment.</strong></p> <p><strong>A candidate gene study was conducted to assess the association of variants within the MHC locus, </strong><strong>coding for different HLA gene subtypes, with carbamazepine-induced subcutaneous adverse reactions </strong><strong>in an ancestrally-European epilepsy case cohort. Together with international colleagues, we identified </strong><strong><em>HLA-A*3101 </em></strong><strong>as a strong predictor of the clinical spectrum of mild to severe subcutaneous adverse </strong><strong>reactions caused by carbamazepine. In a follow-up study, we attempted to replicate our finding in a </strong><strong>similar case cohort caused by exposure to lamotrigine and phenytoin. This study could not detect a </strong><strong>genetic association with any common variant tested, implying the <em>HLA-A*3101 </em>gene is a specific </strong><strong>predictor of carbamazepine-induced adverse events.</strong></p> <p><strong>A genome-wide association study of response to anti-epileptic drugs sought to identify common </strong><strong>variants of large effect that may influence the refractory phenotype witnessed in up to 30% of epilepsy </strong><strong>patients. This study did not detect a genetic association with any common variants tested suggesting </strong><strong>that common variants with smaller effect size, or multiple rare variants may have a role to play. </strong><strong>Finally, we turned our attention to genetic variation that may exist in a number of Irish families with </strong><strong>varied inherited forms of the disease. Using a combination of genome-wide association and whole </strong><strong>exome sequencing, we identified a number of interesting susceptibility genes shared by affected </strong><strong>individuals including an intellectual disability locus, two ion channels and a glucose transporter.</strong></p>