학술논문
Genome-wide determinants of mortality and motor progression in Parkinson’s disease
Document Type
article
Author
Manuela M. X. Tan; Michael A. Lawton; Miriam I. Pollard; Emmeline Brown; Raquel Real; Alejandro Martinez Carrasco; Samir Bekadar; Edwin Jabbari; Regina H. Reynolds; Hirotaka Iwaki; Cornelis Blauwendraat; Sofia Kanavou; Leon Hubbard; Naveed Malek; Katherine A. Grosset; Nin Bajaj; Roger A. Barker; David J. Burn; Catherine Bresner; Thomas Foltynie; Nicholas W. Wood; Caroline H. Williams-Gray; Ole A. Andreassen; Mathias Toft; Alexis Elbaz; Fanny Artaud; Alexis Brice; Jean-Christophe Corvol; Jan Aasly; Matthew J. Farrer; Michael A. Nalls; Andrew B. Singleton; Nigel M. Williams; Yoav Ben-Shlomo; John Hardy; Michele T. M. Hu; Donald G. Grosset; Maryam Shoai; Lasse Pihlstrøm; Huw R. Morris
Source
npj Parkinson's Disease, Vol 10, Iss 1, Pp 1-15 (2024)
Subject
Language
English
ISSN
2373-8057
Abstract
Abstract 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.