ABSTRACT
ABSTRACT Background There are 90 genetic risk variants for Parkinson’s disease (PD) but currently only five nominated loci for PD progression. The biology of PD progression is likely to be of central importance in defining mechanisms that can be used to develop new treatments. Methods We studied 6,766 PD patients, over 15,340 visits with a mean follow-up of between 4.2 and 15.7 years and carried out a genome wide survival study for time to motor progression, defined by reaching Hoehn and Yahr stage 3 or greater, cognitive impairment as defined by serial cognitive examination, and death (mortality). Findings There was a robust effect of the APOE ε4 allele on mortality and cognitive impairment in PD. We identified three novel loci for mortality and motor progression, and nominated genes based on physical proximity or expression quantitative trait loci data. One locus within the TBXAS1 gene encoding thromboxane A synthase 1 was associated with mortality in PD (HR = 2.04 [95% CI 1.63 to 2.56], p-value = 7.71 x 10 -10 ). Another locus near the SYT10 gene encoding synaptotagmin 10 was associated with mortality just above genome-wide significance (HR=1.36 [95% CI 1.21 to 1.51], p-value=5.31×10 -8 ). A genomic variant associated with the expression of ADORA2A , encoding the A2A adenosine receptor, was associated with motor progression (HR=4.83 [95% CI 2.89 to 8.08], p-value=1.94×10 -9 ). Only the non-Gaucher disease causing GBA PD risk variant E326K, of the known PD risk variants, was associated with progression in PD. Interpretation We report three novel loci associated with PD progression or mortality. Further work is needed to understand the links between these genomic variants and the underlying disease biology. However, thromboxane synthesis, vesicular peptidergic neurotransmitter release and the A2A adenosine receptor may represent new candidates for disease modification in PD. RESEARCH IN CONTEXT Evidence before this study We searched PubMed for articles on Parkinson’s disease (PD) with no language restrictions from database inception up to February 9, 2022. We used the search terms “Parkinson disease AND genetics” and “disease progression OR survival OR mortality OR prognosis OR longitudinal studies”. We also conducted this search with the addition of “genome-wide association study” (GWAS) to focus on these genome-wide analyses. There are now three published large-scale GWASs investigating PD progression, and many candidate variant studies. However, no genome-wide studies have reported on survival/mortality in PD. Added value of this study To our knowledge, this is the first GWAS of survival in PD. Our study highlights new loci influencing survival in PD, including TBXAS1 and SYT10 . We also conducted GWASs of progression to other clinical milestones, Hoehn and Yahr stage 3 or greater, and cognitive impairment. We show that APOE influences both mortality and cognitive progression in PD, and report an additional locus influencing expression of ADORA2A which affects the rate of motor progression. Implications of all the available evidence With the exception of APOE , we report new loci which have not been previously associated with PD progression or for mortality and ageing in the general population. These loci could be investigated in functional studies as potential drug targets to stop or slow progression of PD. In addition, new genetic loci can help to improve our understanding of the biology of PD progression and prediction of progression. Further replication of these loci is also needed in independent, longitudinal PD cohorts.