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Genome-Wide Association Studies of Cognitive and Motor Progression in Parkinson's Disease.
Tan, Manuela M X; Lawton, Michael A; Jabbari, Edwin; Reynolds, Regina H; Iwaki, Hirotaka; Blauwendraat, Cornelis; Kanavou, Sofia; Pollard, Miriam I; Hubbard, Leon; Malek, Naveed; Grosset, Katherine A; Marrinan, Sarah L; Bajaj, Nin; Barker, Roger A; Burn, David J; Bresner, Catherine; Foltynie, Thomas; Wood, Nicholas W; Williams-Gray, Caroline H; Hardy, John; Nalls, Michael A; Singleton, Andrew B; Williams, Nigel M; Ben-Shlomo, Yoav; Hu, Michele T M; Grosset, Donald G; Shoai, Maryam; Morris, Huw R.
Afiliación
  • Tan MMX; Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London, London, UK.
  • Lawton MA; UCL Movement Disorders Centre, University College London, London, UK.
  • Jabbari E; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
  • Reynolds RH; Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London, London, UK.
  • Iwaki H; UCL Movement Disorders Centre, University College London, London, UK.
  • Blauwendraat C; Department of Neurodegenerative Diseases, Queen Square Institute of Neurology, University College London, London, UK.
  • Kanavou S; Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.
  • Pollard MI; Data Tecnica International, Glen Echo, Maryland, USA.
  • Hubbard L; Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.
  • Malek N; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
  • Grosset KA; Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London, London, UK.
  • Marrinan SL; MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
  • Bajaj N; Department of Neurology, Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK.
  • Barker RA; Department of Neurology, Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK.
  • Burn DJ; Institute for Ageing and Health, Newcastle University, Newcastle Upon Tyne, UK.
  • Bresner C; Department of Clinical Neurosciences, University of Nottingham, Nottingham, UK.
  • Foltynie T; Department of Clinical Neurosciences, John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK.
  • Wood NW; Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
  • Williams-Gray CH; Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK.
  • Hardy J; MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
  • Nalls MA; Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London, London, UK.
  • Singleton AB; UCL Movement Disorders Centre, University College London, London, UK.
  • Williams NM; Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London, London, UK.
  • Ben-Shlomo Y; UCL Movement Disorders Centre, University College London, London, UK.
  • Hu MTM; Department of Clinical Neurosciences, John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK.
  • Grosset DG; UCL Movement Disorders Centre, University College London, London, UK.
  • Shoai M; Department of Neurodegenerative Diseases, Queen Square Institute of Neurology, University College London, London, UK.
  • Morris HR; Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London, UK.
Mov Disord ; 36(2): 424-433, 2021 02.
Article en En | MEDLINE | ID: mdl-33111402
ABSTRACT

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.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Enfermedad de Parkinson Tipo de estudio: Observational_studies / Prognostic_studies / Risk_factors_studies / Systematic_reviews Límite: Humans Idioma: En Revista: Mov Disord Asunto de la revista: NEUROLOGIA Año: 2021 Tipo del documento: Article País de afiliación: Reino Unido
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Enfermedad de Parkinson Tipo de estudio: Observational_studies / Prognostic_studies / Risk_factors_studies / Systematic_reviews Límite: Humans Idioma: En Revista: Mov Disord Asunto de la revista: NEUROLOGIA Año: 2021 Tipo del documento: Article País de afiliación: Reino Unido