TY - JOUR
T1 - Genome-wide determinants of mortality and motor progression in Parkinson's disease
AU - Tan, Manuela M X
AU - Lawton, Michael A
AU - Pollard, Miriam I
AU - Brown, Emmeline
AU - Real, Raquel
AU - Carrasco, Alejandro Martinez
AU - Bekadar, Samir
AU - Jabbari, Edwin
AU - Reynolds, Regina H
AU - Iwaki, Hirotaka
AU - Blauwendraat, Cornelis
AU - Kanavou, Sofia
AU - Hubbard, Leon
AU - Malek, Naveed
AU - Grosset, Katherine A
AU - Bajaj, Nin
AU - Barker, Roger A
AU - Burn, David J
AU - Bresner, Catherine
AU - Foltynie, Thomas
AU - Wood, Nicholas W
AU - Williams-Gray, Caroline H
AU - Andreassen, Ole A
AU - Toft, Mathias
AU - Elbaz, Alexis
AU - Artaud, Fanny
AU - Brice, Alexis
AU - Corvol, Jean-Christophe
AU - Aasly, Jan
AU - Farrer, Matthew J
AU - Nalls, Michael A
AU - Singleton, Andrew B
AU - Williams, Nigel M
AU - Ben-Shlomo, Yoav
AU - Hardy, John
AU - Hu, Michele T M
AU - Grosset, Donald G
AU - Shoai, Maryam
AU - Pihlstrøm, Lasse
AU - Morris, Huw R
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/6/7
Y1 - 2024/6/7
N2 - There are 90 independent genome-wide significant 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. We studied 6766 PD patients, over 15,340 visits with a mean follow-up of between 4.2 and 15.7 years and carried out genome-wide survival studies for time to a motor progression endpoint, defined by reaching Hoehn and Yahr stage 3 or greater, and death (mortality). There was a robust effect of the APOE ε4 allele on mortality in PD. We also identified a locus within the TBXAS1 gene encoding thromboxane A synthase 1 associated with mortality in PD. We also report 4 independent loci associated with motor progression in or near MORN1, ASNS, PDE5A, and XPO1. Only the non-Gaucher disease causing GBA1 PD risk variant E326K, of the known PD risk variants, was associated with mortality in PD. Further work is needed to understand the links between these genomic variants and the underlying disease biology. However, these may represent new candidates for disease modification in PD.
AB - There are 90 independent genome-wide significant 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. We studied 6766 PD patients, over 15,340 visits with a mean follow-up of between 4.2 and 15.7 years and carried out genome-wide survival studies for time to a motor progression endpoint, defined by reaching Hoehn and Yahr stage 3 or greater, and death (mortality). There was a robust effect of the APOE ε4 allele on mortality in PD. We also identified a locus within the TBXAS1 gene encoding thromboxane A synthase 1 associated with mortality in PD. We also report 4 independent loci associated with motor progression in or near MORN1, ASNS, PDE5A, and XPO1. Only the non-Gaucher disease causing GBA1 PD risk variant E326K, of the known PD risk variants, was associated with mortality in PD. Further work is needed to understand the links between these genomic variants and the underlying disease biology. However, these may represent new candidates for disease modification in PD.
U2 - 10.1038/s41531-024-00729-8
DO - 10.1038/s41531-024-00729-8
M3 - Article (Academic Journal)
C2 - 38849413
SN - 2373-8057
VL - 10
JO - npj Parkinson's Disease
JF - npj Parkinson's Disease
M1 - 113
ER -