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.

Details

Title
Genome-wide determinants of mortality and motor progression in Parkinson’s disease
Author
Tan, Manuela M. X. 1   VIAFID ORCID Logo  ; Lawton, Michael A. 2   VIAFID ORCID Logo  ; Pollard, Miriam I. 3 ; Brown, Emmeline 3 ; Real, Raquel 4   VIAFID ORCID Logo  ; Carrasco, Alejandro Martinez 4   VIAFID ORCID Logo  ; Bekadar, Samir 5 ; Jabbari, Edwin 6   VIAFID ORCID Logo  ; Reynolds, Regina H. 7   VIAFID ORCID Logo  ; Iwaki, Hirotaka 8   VIAFID ORCID Logo  ; Blauwendraat, Cornelis 9   VIAFID ORCID Logo  ; Kanavou, Sofia 2 ; Hubbard, Leon 10 ; Malek, Naveed 11 ; Grosset, Katherine A. 11 ; Bajaj, Nin 12 ; Barker, Roger A. 13   VIAFID ORCID Logo  ; Burn, David J. 14 ; Bresner, Catherine 10   VIAFID ORCID Logo  ; Foltynie, Thomas 6   VIAFID ORCID Logo  ; Wood, Nicholas W. 4   VIAFID ORCID Logo  ; Williams-Gray, Caroline H. 15   VIAFID ORCID Logo  ; Andreassen, Ole A. 16   VIAFID ORCID Logo  ; Toft, Mathias 17 ; Elbaz, Alexis 18   VIAFID ORCID Logo  ; Artaud, Fanny 18 ; Brice, Alexis 5 ; Corvol, Jean-Christophe 5   VIAFID ORCID Logo  ; Aasly, Jan 19 ; Farrer, Matthew J. 20   VIAFID ORCID Logo  ; Nalls, Michael A. 8   VIAFID ORCID Logo  ; Singleton, Andrew B. 9 ; Williams, Nigel M. 10   VIAFID ORCID Logo  ; Ben-Shlomo, Yoav 2 ; Hardy, John 21   VIAFID ORCID Logo  ; Hu, Michele T. M. 22 ; Grosset, Donald G. 23 ; Shoai, Maryam 24   VIAFID ORCID Logo  ; Pihlstrøm, Lasse 25   VIAFID ORCID Logo  ; Morris, Huw R. 4   VIAFID ORCID Logo 

1  Oslo University Hospital, Department of Neurology, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485); University College London, Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, London, UK (GRID:grid.83440.3b) (ISNI:0000 0001 2190 1201); University College London, UCL Movement Disorders Centre, London, UK (GRID:grid.83440.3b) (ISNI:0000 0001 2190 1201) 
2  University of Bristol, Population Health Sciences, Bristol Medical School, Bristol, UK (GRID:grid.5337.2) (ISNI:0000 0004 1936 7603) 
3  University College London, Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, London, UK (GRID:grid.83440.3b) (ISNI:0000 0001 2190 1201) 
4  University College London, Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, London, UK (GRID:grid.83440.3b) (ISNI:0000 0001 2190 1201); University College London, UCL Movement Disorders Centre, London, UK (GRID:grid.83440.3b) (ISNI:0000 0001 2190 1201); Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, USA (GRID:grid.513948.2) (ISNI:0000 0005 0380 6410) 
5  Departement of Neurology, Hôpital Pitié-Salpêtrière, Sorbonne University, Paris Brain Institute - ICM, Inserm, CNRS, Assistance Publique Hôpitaux de Paris, Paris, France (GRID:grid.411439.a) (ISNI:0000 0001 2150 9058) 
6  University College London, Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, London, UK (GRID:grid.83440.3b) (ISNI:0000 0001 2190 1201); University College London, UCL Movement Disorders Centre, London, UK (GRID:grid.83440.3b) (ISNI:0000 0001 2190 1201) 
7  Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, USA (GRID:grid.513948.2) (ISNI:0000 0005 0380 6410); University College London, Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, London, UK (GRID:grid.83440.3b) (ISNI:0000 0001 2190 1201) 
8  National Institutes of Health, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, USA (GRID:grid.94365.3d) (ISNI:0000 0001 2297 5165); Data Tecnica, Washington DC, USA (GRID:grid.94365.3d); National Institutes of Health, Center for Alzheimer’s and Related Dementias, Bethesda, USA (GRID:grid.94365.3d) (ISNI:0000 0001 2297 5165) 
9  National Institutes of Health, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, USA (GRID:grid.94365.3d) (ISNI:0000 0001 2297 5165); National Institutes of Health, Center for Alzheimer’s and Related Dementias, Bethesda, USA (GRID:grid.94365.3d) (ISNI:0000 0001 2297 5165) 
10  Cardiff University, Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff, UK (GRID:grid.5600.3) (ISNI:0000 0001 0807 5670) 
11  Queen Elizabeth University Hospital, Department of Neurology, Institute of Neurological Sciences, Glasgow, UK (GRID:grid.511123.5) (ISNI:0000 0004 5988 7216) 
12  University of Nottingham, Clinical Neurosciences, Nottingham, UK (GRID:grid.4563.4) (ISNI:0000 0004 1936 8868) 
13  Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, USA (GRID:grid.513948.2) (ISNI:0000 0005 0380 6410); University of Cambridge, John Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000 0001 2188 5934); University of Cambridge, Cambridge Stem Cell Institute, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000 0001 2188 5934) 
14  Newcastle University, Faculty of Medical Sciences, Newcastle upon Tyne, UK (GRID:grid.1006.7) (ISNI:0000 0001 0462 7212) 
15  University of Cambridge, John Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000 0001 2188 5934) 
16  Oslo University Hospital, NORMENT, Division of Mental Health and Addiction, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485); University of Oslo, Institute of Clinical Medicine, Faculty of Medicine, Oslo, Norway (GRID:grid.5510.1) (ISNI:0000 0004 1936 8921) 
17  Oslo University Hospital, Department of Neurology, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485); University of Oslo, Institute of Clinical Medicine, Faculty of Medicine, Oslo, Norway (GRID:grid.5510.1) (ISNI:0000 0004 1936 8921) 
18  “Exposome and Heredity” team, CESP, Paris-Saclay University, UVSQ, Inserm, Gustave Roussy, Villejuif, France (GRID:grid.463845.8) (ISNI:0000 0004 0638 6872) 
19  St. Olavs Hospital, Department of Neurology, Trondheim, Norway (GRID:grid.52522.32) (ISNI:0000 0004 0627 3560); Norwegian University of Science and Technology (NTNU), Department of Neuromedicine and Movement Science (INB), Faculty of Medicine and Health Sciences, Trondheim, Norway (GRID:grid.5947.f) (ISNI:0000 0001 1516 2393) 
20  University of Florida, Department of Neurology, Gainesville, USA (GRID:grid.15276.37) (ISNI:0000 0004 1936 8091) 
21  University College London, UCL Movement Disorders Centre, London, UK (GRID:grid.83440.3b) (ISNI:0000 0001 2190 1201); Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, USA (GRID:grid.513948.2) (ISNI:0000 0005 0380 6410); University College London, Department of Neurodegenerative Diseases, Queen Square Institute of Neurology, London, UK (GRID:grid.83440.3b) (ISNI:0000 0001 2190 1201); UCL Queen Square Institute of Neurology, Reta Lila Weston Institute, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201); University College London, UK Dementia Research Institute, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201); National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre, London, UK (GRID:grid.451056.3) (ISNI:0000 0001 2116 3923); The Hong Kong University of Science and Technology, Institute for Advanced Study, Hong Kong SAR, China (GRID:grid.24515.37) (ISNI:0000 0004 1937 1450) 
22  University of Oxford, Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, Oxford, UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948); University of Oxford, Oxford Parkinson’s Disease Centre, Oxford, UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948); Oxford University Hospitals NHS Foundation Trust, Department of Clinical Neurology, Oxford, UK (GRID:grid.410556.3) (ISNI:0000 0001 0440 1440) 
23  University of Glasgow, School of Neuroscience and Psychology, Glasgow, UK (GRID:grid.8756.c) (ISNI:0000 0001 2193 314X) 
24  Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, USA (GRID:grid.513948.2) (ISNI:0000 0005 0380 6410); University College London, Department of Neurodegenerative Diseases, Queen Square Institute of Neurology, London, UK (GRID:grid.83440.3b) (ISNI:0000 0001 2190 1201); UCL Queen Square Institute of Neurology, Reta Lila Weston Institute, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201) 
25  Oslo University Hospital, Department of Neurology, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485) 
Pages
113
Publication year
2024
Publication date
2024
Publisher
Nature Publishing Group
e-ISSN
23738057
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41531-024-00729-8
ProQuest document ID
3065479810
Copyright
© The Author(s) 2024. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.