Caruana Galizia, E; (2017) A pharmacogenetic study in epilepsy. Doctoral thesis , UCL (University College London).

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Abstract

Pharmacogenetics is a rapidly expanding field in epilepsy but work to date has failed to show clear associations with distinct responses to anti-epileptic drugs. This thesis describes a pharmacogenetic study in epilepsy that explores: 1 . Current definitions of drug-response in epilepsy and their limitations in the context of pharmacogenetic studies. 2 . Different methods for defining drug response using a combination of visualization and data-reducing techniques and how these techniques facilitate grouping of similar responses while identifying those that do not conform to any particular pattern. 3 . The hypotheses that common or rare genetic variation may be associated with a particular response pattern in a cohort treated with the anti-epileptic drug (AED) levetiracetam. 4. The hypothesis that rare genetic variation may be associated with adverse behavioural events due to levetiracetam. The primary findings from this thesis may be summarised as follows: 1 . Use of traditional methods for classifying drug-response is over-simplistic and fails to take account of the complexity of drug-response in epilepsy. Guidelines for defining seizure-freedom also fall short in identifying individuals who remain seizure-free. 2 . Visualisation and data-reducing techniques demonstrate that drug response forms a spectrum and the use of these different techniques allows grouping of the most similar response profiles. 3 . A genome-wide association study did not show an association between response to levetiracetam and common genetic variation; a candidate gene study failed to identify rare variation associated with response to levetiracetam. A signal that did not reach significance levels was observed when comparing people that stopped levetiracetam early due to side effects, to those that stopped levetiracetam later. 4. A greater burden of rare variants was identified in patients with severe adverse behavioural events due to levetiracetam.

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