Meta-Analysis

. 2021 Feb;36(2):424-433.

doi: 10.1002/mds.28342. Epub 2020 Oct 28.

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

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.

PMID: 33111402
PMCID: PMC9053517
DOI: 10.1002/mds.28342

Meta-Analysis

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

Manuela M X Tan et al. Mov Disord. 2021 Feb.

. 2021 Feb;36(2):424-433.

doi: 10.1002/mds.28342. Epub 2020 Oct 28.

Authors

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.

PMID: 33111402
PMCID: PMC9053517
DOI: 10.1002/mds.28342

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.

PubMed Disclaimer

Conflict of interest statement

Relevant conflicts of interest/financial disclosures: None to report.

Figures

**Fig. 1.**
Steps to create composite, motor, and congnitive progression scores. AAO, age at onset. [Color figure can be viewed at wileyonlinelibrary.com]

**FIG. 2.**
Manhattan plot for GWAS of composite progression. The red dashed line indicates the genome-wide significance threshold, P = 5×10⁻⁸. The top genes from the MAGMA gene-based analysis and P values are shown on the right. [Color figure can be viewed at wileyonlinelibrary.com]

**FIG. 3.**
Manhattan plot for the GWAS of motor progression. Genome-wide significance is the standard P = 5 × 10⁻⁸ (not indicated in the figure). The top genes from the MAGMA gene-based analysis and P values are shown on the right. [Color figure can be viewed at wileyonlinelibrary.com]

**FIG. 4.**
Manhattan plot for the variant-based GWAS of cognitive progression. The red dashed line indicates the genome-wide significance threshold, P = 5×10⁻⁸. The top genes from the MAGMA gene-based analysis and P values are shown on the right. [Color figure can be viewed at wileyonlinelibrary.com]

See this image and copyright information in PMC

References

1. Williams-Gray CH, Mason SL, Evans JR, et al. The CamPaIGN study of Parkinson’s disease: 10-year outlook in an incident population-based cohort. J Neurol Neurosurg Psychiatry 2013;84: 1258–1264. - PubMed
1. Nalls MA, Blauwendraat C, Vallerga CL, et al. Identification of novel risk loci, causal insights, and heritable risk for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet Neurol 2019;18( 12):1091–1102. - PMC - PubMed
1. Maetzler W, Liepelt I, Berg D. Progression of Parkinson’s disease in the clinical phase: potential markers. Lancet Neurol 2009;8(12): 1158–1171. - PubMed
1. Evers LJW, Krijthe JH, Meinders MJ, Bloem BR, Heskes TM. Measuring Parkinson’s disease over time: the real-world within-subject reliability of the MDS-UPDRS. Mov Disord 2019;34(10): 1480–1487. - PMC - PubMed
1. Kerr GK, Worringham CJ, Cole MH, Lachcrcz PF, Wood JM, Silbum PA. Predictors of future falls in Parkinson disease. Neurology 2010;75(2):116–124. - PubMed

Publication types

Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous