npj Parkinson's Disease (Jun 2024)
Genome-wide determinants of mortality and motor progression in Parkinson’s disease
- 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
Affiliations
- Manuela M. X. Tan
- Department of Neurology, Oslo University Hospital
- Michael A. Lawton
- Population Health Sciences, Bristol Medical School, University of Bristol
- Miriam I. Pollard
- Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London
- Emmeline Brown
- Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London
- Raquel Real
- Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London
- Alejandro Martinez Carrasco
- Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London
- Samir Bekadar
- Sorbonne University, Paris Brain Institute - ICM, Inserm, CNRS, Assistance Publique Hôpitaux de Paris, Departement of Neurology, Hôpital Pitié-Salpêtrière
- Edwin Jabbari
- Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London
- Regina H. Reynolds
- Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network
- Hirotaka Iwaki
- Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health
- Cornelis Blauwendraat
- Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health
- Sofia Kanavou
- Population Health Sciences, Bristol Medical School, University of Bristol
- Leon Hubbard
- Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University
- Naveed Malek
- Department of Neurology, Institute of Neurological Sciences, Queen Elizabeth University Hospital
- Katherine A. Grosset
- Department of Neurology, Institute of Neurological Sciences, Queen Elizabeth University Hospital
- Nin Bajaj
- Clinical Neurosciences, University of Nottingham
- Roger A. Barker
- Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network
- David J. Burn
- Faculty of Medical Sciences, Newcastle University
- Catherine Bresner
- Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University
- Thomas Foltynie
- Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London
- Nicholas W. Wood
- Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London
- Caroline H. Williams-Gray
- John Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge
- Ole A. Andreassen
- NORMENT, Division of Mental Health and Addiction, Oslo University Hospital
- Mathias Toft
- Department of Neurology, Oslo University Hospital
- Alexis Elbaz
- Paris-Saclay University, UVSQ, Inserm, Gustave Roussy, “Exposome and Heredity” team, CESP
- Fanny Artaud
- Paris-Saclay University, UVSQ, Inserm, Gustave Roussy, “Exposome and Heredity” team, CESP
- Alexis Brice
- Sorbonne University, Paris Brain Institute - ICM, Inserm, CNRS, Assistance Publique Hôpitaux de Paris, Departement of Neurology, Hôpital Pitié-Salpêtrière
- Jean-Christophe Corvol
- Sorbonne University, Paris Brain Institute - ICM, Inserm, CNRS, Assistance Publique Hôpitaux de Paris, Departement of Neurology, Hôpital Pitié-Salpêtrière
- Jan Aasly
- Department of Neurology, St. Olavs Hospital
- Matthew J. Farrer
- Department of Neurology, University of Florida
- Michael A. Nalls
- Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health
- Andrew B. Singleton
- Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health
- Nigel M. Williams
- Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University
- Yoav Ben-Shlomo
- Population Health Sciences, Bristol Medical School, University of Bristol
- John Hardy
- UCL Movement Disorders Centre, University College London
- Michele T. M. Hu
- Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, University of Oxford
- Donald G. Grosset
- School of Neuroscience and Psychology, University of Glasgow
- Maryam Shoai
- Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network
- Lasse Pihlstrøm
- Department of Neurology, Oslo University Hospital
- Huw R. Morris
- Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London
- DOI
- https://doi.org/10.1038/s41531-024-00729-8
- Journal volume & issue
-
Vol. 10,
no. 1
pp. 1 – 15
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.
