Genome-wide determinants of mortality and clinical progression in Parkinson's disease

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 {epsilon}4 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=5.31x10-8). 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=1.94x10-9). 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.