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

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=5.31x10-8). 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.

Limited overlap between genetic effects on disease susceptibility and disease survival

“…Our approach aims to compare progression across multiple diseases and comes at expenses of a tailored definition of progression for each disease. Nonetheless, disease-specific mortality has been widely used as a measure of progression (Hernesniemi, 2022; Jabbari et al, 2021; Tan et al, 2022; Wu et al, 2014). In practice, biobank-based studies of disease progression often need to converge to simple definitions to maximise sample size, and disease-specific mortality is an information typically available across biobanks.…”

“…Among neurological conditions, GWAS have focused on disease survival as well as cognitive or motor decline. In one of the largest studies, researchers have identified three novel loci associated with Parkinson’s disease progression (Tan et al, 2022). A recent study on multiple sclerosis progression has identified a locus pointing to involvement of the central nervous system in disease outcome as opposed to the enrichment for immunological-related signals observed for disease susceptibility (Harroud et al, 2023).…”

Multifactorial assessment of Parkinson’s disease course and outcomes using trajectory modeling in a multiethnic, multisite cohort – extension of the LONG-PD study

“… Liu et al (2021) , in a study of 3,821 patients, identified three novel loci associated with cognitive progression in PD, in addition to confirming associations with GBA1 and APOE. Tan et al (2022) , in an analysis of 11 cohorts from Europe and the Americas, including the PPMI, Tracking Parkinson’s, and Oxford Discovery cohorts ( Lawton et al, 2022 ), identified six novel loci associated with PD motor progression or mortality, and found that the E326K GBA1 variant was associated with increased mortality. Martínez Carrasco et al (2023) , in a GWAS meta-analysis, identified an association between axial motor progression and expression of ACP6 that suggests mitochondrial lipid homeostasis plays a role in motor progression.…”