UBC Theses and Dissertations
Associations of DNA methylation with individual differences in Parkinson's disease susceptibility Schaffner, Samantha Lynn
Parkinson’s disease (PD) is a common neurodegenerative disorder with increasing worldwide prevalence. Although a number of genes and environmental factors influencing PD susceptibility have been identified, the mechanisms underpinning their joint contributions to disease pathogenesis are not fully understood. DNA methylation (DNAm) is an epigenetic mark that is sensitive to genetics and environment and can influence gene transcription. Due to these properties, DNAm has been proposed as a contributor to PD etiology and also as a potential early-stage biomarker. However, the complex interindividual etiology of PD and the inability to its study progression in human brain tissue present challenges in researching the role of DNAm in PD pathogenesis. In this dissertation, I investigated the associations of DNAm with genetic and environmental factors influencing PD susceptibility and with early-stage PD in human populations. Using a human dopaminergic neuron cell line, I found that overexpressing the wild type or A30P mutant form of the SNCA gene induced thousands of site-specific DNAm changes. These DNAm changes were associated with altered DNA hydroxymethylation (DNAhm) and transcription of glutamate signaling genes. Additionally, I investigated the impacts of overexpressing wild type SNCA in mice housed in a standard or enriched environment paradigm by profiling hippocampal DNAm and DNAhm, and integrating these results with previously generated RNA-seq and ChIP-seq (H3K4me1, H3K4me3, H3K27ac). SNCA overexpression was associated with similar DNAhm and H3K27ac alterations when mice were housed in a standard or enriched environment, and with environment-dependent changes to H3K4 and DNA methylation. In particular, environment prevented some SNCA-induced changes to H3K4me1, a select few of which correlated with gene expression. Finally, I investigated the contributions of sex, genetic background, and pesticide exposure to blood DNAm signatures of early-stage PD in a sample of 218 agricultural workers and their spouses. Differentially methylated regions associated with early-stage PD differed by sex and were influenced by genetic background to a greater degree than pesticide exposure. Altogether, I have enhanced our understanding of the impacts of PD-associated genotypes and environments on the brain and blood epigenome, and laid a foundation for further studies of the role of the epigenome in PD etiology.
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