Genome-wide determinants of mortality and motor progression in Parkinson’s disease


ABSTRACTBackgroundThere 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.MethodsWe 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 a motor progression endpoint, defined by reaching Hoehn and Yahr stage 3 or greater, and death (mortality).FindingsThere was a robust effect of theAPOEε4 allele on mortality in PD. We identified three novel loci for mortality and motor progression, and nominated genes based on physical proximity and/or expression quantitative trait loci data. One locus within theTBXAS1gene 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 theSYT10gene 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). We also report 4 independent loci associated with motor progression: the top locus withinMORN1(HR=2.76 [95% CI 1.97 to 3.87], p-value=3.1×10-9), the second most significant locus nearASNS, the third most significant locus nearPDE5A, and a fourth locus withinXPO1. We have nominated causal genes based on physical position, however we also discuss other possible causal genes based on expression quantitative trait loci, colocalization analysis, and tagging of rare variants. Only the non-Gaucher disease causingGBA1PD risk variant E326K, of the known PD risk variants, was associated with mortality in PD.InterpretationWe report six novel loci associated with PD motor 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 phosphodiesterase inhibition may represent new candidates for disease modification in PD.Funding sourcesParkinson’s UK, Aligning Science Across Parkinson’s through the Michael J Fox Foundation for Parkinson’s Research, Southern and Eastern Norway Regional Health Authority