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

DOI: http://doi.org/10.1101/2022.07.07.22277297 Journal: E-pub date: 1 Aug 2022 Authors: MMX Tan, MA Lawton, MI Pollard, E Brown, R Real, A Martinez Carrasco, S Bekadar, E Jabbari, RH Reynolds, H Iwaki, C Blauwendraat, S Kanavou, L Hubbard, N Malek, KA Grosset, N Bajaj, RA Barker, DJ Burn, C Bresner, T Foltynie, NW Wood, CH Williams-Gray, OA Andreassen, M Toft, A Elbaz, F Artaud, A Brice, J-C Corvol, J Aasly, MJ Farrer, MA Nalls, AB Singleton, NM Williams, Y Ben-Shlomo, J Hardy, MTM Hu, DG Grosset, M Shoai, L Pihlstrøm, HR Morris

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

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 a motor progression endpoint, defined by reaching Hoehn and Yahr stage 3 or greater, and death (mortality).

Findings

There was a robust effect of the APOE ε4 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 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 ). We also report 4 independent loci associated with motor progression: the top locus within MORN1 (HR=2.76 [95% CI 1.97 to 3.87], p-value=3.1×10 -9 ), the second most significant locus near ASNS , the third most significant locus near PDE5A , and a fourth locus within XPO1 . 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 causing GBA1 PD risk variant E326K, of the known PD risk variants, was associated with mortality in PD.

Interpretation

We 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 sources

Parkinson’s UK, Aligning Science Across Parkinson’s through the Michael J Fox Foundation for Parkinson’s Research, Southern and Eastern Norway Regional Health Authority