Identifying genetic determinants of progression in Parkinson's disease

Parkinson’s disease (PD) is a progressive neurodegenerative condition for which there are currently no treatments to stop or slow disease progression. A number of genome-wide association studies (GWASs) of PD patients compared to controls have identified genetic variants associated with disease risk, however these cannot inform us about the genetic factors and biology underpinning progression. The aim of this PhD is to identify genetic variants associated with disease progression. I first examined the frequency and baseline clinical features of patients carrying rare pathogenic Mendelian mutations (including variants in LRRK2, SNCA, Parkin, and PINK1) in the Tracking Parkinson’s cohort. I showed that Parkin and PINK1 carriers had better cognition than other early-onset patients at baseline despite having longer disease duration, suggesting slower progression. In analysis of longitudinal data, I also showed that GBA carriers appeared to have more rapid motor and cognitive progression than non-carriers. Prior to conducting GWASs, I sought to understand the clinical predictors of progression and showed that age at onset and gender were associated with progression to clinical milestones. Following a new method from the Huntington’s disease progression GWAS, I used principal components analysis (PCA) to combine multiple motor and cognitive scales in PD to create composite progression scores. I showed that APOE ε4 was strongly associated with cognitive progression, and identified a novel signal in ATP8B2 which was nominally associated with motor progression. Finally, I conducted large-scale GWASs of survival to clinical milestones: mortality, Hoehn and Yahr stage 3, and dementia, using data from Tracking Parkinson’s, Oxford Discovery, Parkinson’s Progression Markers Initiative, Queen Square Brain Bank, UK Biobank, and Calypso studies. I identified loci in or near APOE, ADRA2A, and SH3GL2 which were nominally associated with progression to mortality. I also showed that the APOE ε4 variant, rs429358, was strongly associated with progression to dementia