Year: 2024
Type: article
Study design: Observational Study
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
Source: npj Parkinson s Disease
Authors: 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
Institutions: Oslo University Hospital, UCL Queen Square Institute of Neurology, University College London, University of Bristol, Aligning Science Across Parkinson's, Centre National de la Recherche Scientifique, Inserm, Sorbonne Université, Assistance Publique – Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Institut du Cerveau, National Institutes of Health, National Institute on Aging, Cardiff University, Queen Elizabeth University Hospital, University of Nottingham, Wellcome/MRC Cambridge Stem Cell Institute, University of Cambridge, Newcastle University, University of Oslo, Université de Versailles Saint-Quentin-en-Yvelines, Centre de recherche en Epidémiologie et Santé des Populations, Norwegian University of Science and Technology, St Olav's University Hospital, University of Florida Health, University of Florida, Hong Kong University of Science and Technology, National Institute for Health and Care Research, UK Dementia Research Institute, UCL Biomedical Research Centre, University of Oxford, Oxford University Hospitals NHS Trust, University of Glasgow
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,590
OpenAlex ID: W4399432024