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

Manuela M X Tan; Michael A Lawton; Edwin Jabbari; Regina H Reynolds; Hirotaka Iwaki; Cornelis Blauwendraat; Sofia Kanavou; Miriam I Pollard; Leon Hubbard; Naveed Malek; Katherine A Grosset; Sarah L Marrinan; Nin Bajaj; Roger A Barker; David J Burn; Catherine Bresner; Thomas Foltynie; Nicholas W Wood; Caroline H Williams-Gray; John Hardy; Michael A Nalls; Andrew B Singleton; Nigel M Williams; Yoav Ben-Shlomo; Michele T M Hu; Donald G Grosset; Maryam Shoai; Huw R Morris

doi:10.1002/mds.28342

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

Mov Disord. 2021 Feb;36(2):424-433. doi: 10.1002/mds.28342. Epub 2020 Oct 28.

Authors

Manuela M X Tan^{1

2}, Michael A Lawton³, Edwin Jabbari^{1

2}, Regina H Reynolds⁴, Hirotaka Iwaki^{5

6}, Cornelis Blauwendraat⁵, Sofia Kanavou³, Miriam I Pollard¹, Leon Hubbard⁷, Naveed Malek⁸, Katherine A Grosset⁸, Sarah L Marrinan⁹, Nin Bajaj¹⁰, Roger A Barker^{11

12}, David J Burn¹³, Catherine Bresner⁷, Thomas Foltynie^{1

2}, Nicholas W Wood^{1

2}, Caroline H Williams-Gray¹¹, John Hardy^{2

4

14

15

16

17}, Michael A Nalls^{5

6}, Andrew B Singleton⁵, Nigel M Williams⁷, Yoav Ben-Shlomo³, Michele T M Hu^{18

19

20}, Donald G Grosset⁸, Maryam Shoai^{4

15}, Huw R Morris^{1

2}

Affiliations

¹ Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London, London, UK.
² UCL Movement Disorders Centre, University College London, London, UK.
³ Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
⁴ Department of Neurodegenerative Diseases, Queen Square Institute of Neurology, University College London, London, UK.
⁵ Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.
⁶ Data Tecnica International, Glen Echo, Maryland, USA.
⁷ MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
⁸ Department of Neurology, Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK.
⁹ Institute for Ageing and Health, Newcastle University, Newcastle Upon Tyne, UK.
¹⁰ Department of Clinical Neurosciences, University of Nottingham, Nottingham, UK.
¹¹ Department of Clinical Neurosciences, John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK.
¹² Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
¹³ Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK.
¹⁴ Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London, UK.
¹⁵ UK Dementia Research Institute, University College London, London, UK.
¹⁶ National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre, London, UK.
¹⁷ Institute for Advanced Study, The Hong Kong University of Science and Technology, Hong Kong, SAR, China.
¹⁸ Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, University of Oxford, Oxford, UK.
¹⁹ Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK.
²⁰ Department of Clinical Neurology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.

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.

Keywords: Parkinson's disease; genetics; genome-wide association study; progression.

Publication types

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

MeSH terms

Biomarkers
Cognition
Disease Progression
Genome-Wide Association Study
Humans
Parkinson Disease* / genetics

Substances

Biomarkers

Abstract

Publication types

MeSH terms

Substances

Grants and funding