Genome-Wide Association Studies of Cognitive and Motor Progression in Parkinson's Disease.

Autor: Tan MMX; Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London, London, UK.; UCL Movement Disorders Centre, University College London, London, UK., Lawton MA; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK., Jabbari E; Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London, London, UK.; UCL Movement Disorders Centre, University College London, London, UK., Reynolds RH; Department of Neurodegenerative Diseases, Queen Square Institute of Neurology, University College London, London, UK., Iwaki H; Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.; Data Tecnica International, Glen Echo, Maryland, USA., Blauwendraat C; Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA., Kanavou S; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK., Pollard MI; Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London, London, UK., Hubbard L; MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK., Malek N; Department of Neurology, Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK., Grosset KA; Department of Neurology, Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK., Marrinan SL; Institute for Ageing and Health, Newcastle University, Newcastle Upon Tyne, UK., Bajaj N; Department of Clinical Neurosciences, University of Nottingham, Nottingham, UK., Barker RA; Department of Clinical Neurosciences, John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK.; Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK., Burn DJ; Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK., Bresner C; MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK., Foltynie T; Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London, London, UK.; UCL Movement Disorders Centre, University College London, London, UK., Wood NW; Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London, London, UK.; UCL Movement Disorders Centre, University College London, London, UK., Williams-Gray CH; Department of Clinical Neurosciences, John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK., Hardy J; UCL Movement Disorders Centre, University College London, London, UK.; Department of Neurodegenerative Diseases, Queen Square Institute of Neurology, University College London, London, UK.; Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London, UK.; UK Dementia Research Institute, University College London, London, UK.; National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre, London, UK.; Institute for Advanced Study, The Hong Kong University of Science and Technology, Hong Kong, SAR, China., Nalls MA; Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.; Data Tecnica International, Glen Echo, Maryland, USA., Singleton AB; Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA., Williams NM; MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK., Ben-Shlomo Y; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK., Hu MTM; Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, University of Oxford, Oxford, UK.; Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK.; Department of Clinical Neurology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK., Grosset DG; Department of Neurology, Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK., Shoai M; Department of Neurodegenerative Diseases, Queen Square Institute of Neurology, University College London, London, UK.; UK Dementia Research Institute, University College London, London, UK., Morris HR; Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London, London, UK.; UCL Movement Disorders Centre, University College London, London, UK.
Jazyk: angličtina
Zdroj: Movement disorders : official journal of the Movement Disorder Society [Mov Disord] 2021 Feb; Vol. 36 (2), pp. 424-433. Date of Electronic Publication: 2020 Oct 28.
DOI: 10.1002/mds.28342
Abstrakt: Background: There are currently no treatments that stop or slow the progression of Parkinson's disease (PD). Case-control genome-wide association studies have identified variants associated with disease risk, but not progression. The objective of the current study was to identify genetic variants associated with PD progression.
Methods: We analyzed 3 large longitudinal cohorts: Tracking Parkinson's, Oxford Discovery, and the Parkinson's Progression Markers Initiative. We included clinical data for 3364 patients with 12,144 observations (mean follow-up 4.2 years). We used a new method in PD, following a similar approach in Huntington's disease, in which we combined multiple assessments using a principal components analysis to derive scores for composite, motor, and cognitive progression. These scores were analyzed in linear regression in genome-wide association studies. We also performed a targeted analysis of the 90 PD risk loci from the latest case-control meta-analysis.
Results: There was no overlap between variants associated with PD risk, from case-control studies, and PD age at onset versus PD progression. The APOE ε4 tagging variant, rs429358, was significantly associated with composite and cognitive progression in PD. Conditional analysis revealed several independent signals in the APOE locus for cognitive progression. No single variants were associated with motor progression. However, in gene-based analysis, ATP8B2, a phospholipid transporter related to vesicle formation, was nominally associated with motor progression (P = 5.3 × 10 -6 ).
Conclusions: We provide early evidence that this new method in PD improves measurement of symptom progression. We show that the APOE ε4 allele drives progressive cognitive impairment in PD. Replication of this method and results in independent cohorts are needed. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
(© 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)
Databáze: MEDLINE
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