Identification of genetic factors underpinning phenotypic heterogeneity in Huntington's disease and other neurodegenerative disorders

Neurodegenerative diseases including Huntington’s disease (HD), the spinocerebellar ataxias and C9orf72 associated Amyotrophic Lateral Sclerosis / Frontotemporal dementia (ALS/FTD) do not present and progress in the same way in all patients. Instead there is phenotypic variability in age at onset, progression and symptoms. Understanding this variability is not only clinically valuable, but identification of the genetic factors underpinning this variability has the potential to highlight genes and pathways which may be amenable to therapeutic manipulation, hence help find drugs for these devastating and currently incurable diseases. Identification of genetic modifiers of neurodegenerative diseases is the overarching aim of this thesis. To identify genetic variants which modify disease progression it is first necessary to have a detailed characterization of the disease and its trajectory over time. In this thesis clinical data from the TRACK-HD studies, for which I collected data as a clinical fellow, was used to study disease progression over time in HD, and give subjects a progression score for subsequent analysis. In this thesis I show blood transcriptomic signatures of HD status and stage which parallel HD brain and overlap with Alzheimer’s disease brain. Using the Huntington’s disease progression score in a genome wide association study, both a locus on chromosome 5 tagging MSH3, and DNA handling pathways more broadly, are shown to modify HD progression: these results are explored. Transcriptomic signatures associated with HD progression rate are also investigated. In this thesis I show that DNA repair variants also modify age at onset in spinocerebellar ataxias (1, 2, 3, 6, 7 and 17), which are, like HD, caused by triplet repeat expansions, suggesting a common mechanism. Extending this thesis’ examination of the relationship between phenotype and genotype I show that the C9orf72 expansion, normally associated with ALS/FTD, is also the commonest cause of HD phenocopy presentations