Cavalleri, G.L.; (2006) Haplotype mapping in epilepsy genetics and pharmacogenetics. Doctoral thesis , University of London.

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Abstract

Despite the success achieved in identifying mutations causing Mendelian forms of epilepsy, little progress has been made in illuminating variation contributing to the development of more common forms of the condition. The aim of this thesis was to improve methodology that would aid the detection of variation functional in the development and treatment of common forms of epilepsy. Attempted replication of previous claims of association with common forms of epilepsy allowed resolution of true effects from false positive results and illustrated shortcomings in the application of association based genetic mapping. Where effects looked real, haplotype-based fine mapping techniques were applied to identify candidate causal variation. The tagging SNP method was applied to HapMap data in an attempt to identify variation that might guide the safe prescription of Vigabatrin, an effective antiepileptic drug limited by a serious adverse drug reaction. Results outlined here show all previous claims of association with temporal lobe epilepsy and febrile seizures are likely to be false positives. However, supportive evidence is presented that common genetic variation predisposes to juvenile myoclonic epilepsy in a population specific manner. Evidence is also presented that variation that could be considered clinically relevant for the safe administration of Vigabatrin does not exist in the candidate genes examined here. Finally, a study design is proposed that seeks to significantly increase genetic power of detection through the incorporation of lessons learned from previous studies. In conclusion, epilepsy appears to be as genetically complex as the phenotypic spectrum of the condition would suggest. This work illustrates key areas in study design that require improvement and presents methodological developments in genetic mapping techniques which together provide a solid platform for future success.

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