Date of Award
PhD (Doctor of Philosophy)
Dr Gianpiero L. Cavalleri
Dr Norman Delanty
Health Research Board in Ireland
Epilepsy, Genetics, Genetic Association Studies
There is an increasing amount of evidence to suggest genetics plays a large role in governing an individual's risk for developing epilepsy and their response to anti-epileptic drug treatment. Responses can range from seizure control with first drug, complete resistance and serious idiopathic and doserelated adverse events occurring upon exposure to specific drugs. This thesis consists of five studies with a common aim of identifying novel genetic influences on epilepsy predisposition and treatment.
A candidate gene study was conducted to assess the association of variants within the MHC locus, coding for different HLA gene subtypes, with carbamazepine-induced subcutaneous adverse reactions in an ancestrally-European epilepsy case cohort. Together with international colleagues, we identified HLA-A*3101 as a strong predictor of the clinical spectrum of mild to severe subcutaneous adverse reactions caused by carbamazepine. In a follow-up study, we attempted to replicate our finding in a similar case cohort caused by exposure to lamotrigine and phenytoin. This study could not detect a genetic association with any common variant tested, implying the HLA-A*3101 gene is a specific predictor of carbamazepine-induced adverse events.
A genome-wide association study of response to anti-epileptic drugs sought to identify common variants of large effect that may influence the refractory phenotype witnessed in up to 30% of epilepsy patients. This study did not detect a genetic association with any common variants tested suggesting that common variants with smaller effect size, or multiple rare variants may have a role to play. Finally, we turned our attention to genetic variation that may exist in a number of Irish families with varied inherited forms of the disease. Using a combination of genome-wide association and whole exome sequencing, we identified a number of interesting susceptibility genes shared by affected individuals including an intellectual disability locus, two ion channels and a glucose transporter.
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McCormack M. Genome-wide mapping of markers for epilepsy predisposition and treatment. [PhD Thesis]. Dublin: Royal College of Surgeons in Ireland; 2013.