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

Biomarkers Cognition Disease Progression Genome-Wide Association Study Humans Parkinson Disease / genetics
Parkinson's disease genetics genome-wide association study progression

Journal

Movement disorders : official journal of the Movement Disorder Society
ISSN: 1531-8257
Titre abrégé: Mov Disord
Pays: United States
ID NLM: 8610688

Informations de publication

Date de publication:
02 2021
Historique:
received: 29 04 2020
revised: 10 09 2020
accepted: 05 10 2020
pubmed: 29 10 2020
medline: 28 4 2021
entrez: 28 10 2020
Statut: ppublish

Résumé

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. 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. 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 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.

Sections du résumé

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
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.

Identifiants

DOI: 10.1002/mds.28342 PMID: 33111402 PMC: PMC9053517
pubmed: 33111402
doi: 10.1002/mds.28342
pmc: PMC9053517
mid: NIHMS1788954
doi:

Substances chimiques

Biomarkers 0

Types de publication

Journal Article Meta-Analysis Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

424-433

Subventions

Organisme : Medical Research Council
ID : MR/R007446/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L010305/1
Pays : United Kingdom
Organisme : Parkinson's UK
ID : H-1703
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/N026004/1
Pays : United Kingdom
Organisme : Intramural NIH HHS
ID : Z01 AG000949
Pays : United States
Organisme : Parkinson's UK
ID : J-0901
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_EX_MR/N50192X/1
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/S000992/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0700943
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/M024962/1
Pays : United Kingdom

Informations de copyright

© 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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Auteurs

Manuela M X 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.
ORCID: 0000-0001-5835-669X

Michael A Lawton (MA)

Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.

Edwin 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.
ORCID: 0000-0001-6844-882X

Regina H Reynolds (RH)

Department of Neurodegenerative Diseases, Queen Square Institute of Neurology, University College London, London, UK.

Hirotaka 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.
ORCID: 0000-0002-8982-7885

Cornelis Blauwendraat (C)

Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.

Sofia Kanavou (S)

Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.

Miriam I Pollard (MI)

Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London, London, UK.

Leon Hubbard (L)

MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.

Naveed Malek (N)

Department of Neurology, Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK.

Katherine A Grosset (KA)

Department of Neurology, Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK.

Sarah L Marrinan (SL)

Institute for Ageing and Health, Newcastle University, Newcastle Upon Tyne, UK.

Nin Bajaj (N)

Department of Clinical Neurosciences, University of Nottingham, Nottingham, UK.

Roger A 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.

David J Burn (DJ)

Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK.

Catherine Bresner (C)

MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.

Thomas 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.
ORCID: 0000-0003-0752-1813

Nicholas W 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.

Caroline H Williams-Gray (CH)

Department of Clinical Neurosciences, John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK.
ORCID: 0000-0002-2648-9743

John 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.

Michael A 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.

Andrew B Singleton (AB)

Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.

Nigel M Williams (NM)

MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.

Yoav Ben-Shlomo (Y)

Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.

Michele T M 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.

Donald G Grosset (DG)

Department of Neurology, Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK.

Maryam 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.

Huw R 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.
ORCID: 0000-0002-5473-3774

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Classifications MeSH

questionsmedicales.fr › Facteurs biologiques › Marqueurs biologiques › Genome-Wide Association Studies of Cognitive...
questionsmedicales.fr › Phénomènes psychologiques › Processus mentaux › Cognition › Genome-Wide Association Studies of Cognitive...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Caractéristiques de la maladie › Évolution de la maladie › Genome-Wide Association Studies of Cognitive...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Épidémiologie moléculaire › Étude d'association pangénomique › Genome-Wide Association Studies of Cognitive...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Genome-Wide Association Studies of Cognitive...
questionsmedicales.fr › Maladies du système nerveux › Maladies neurodégénératives › Maladie de Parkinson › Genome-Wide Association Studies of Cognitive...