Journal
MOVEMENT DISORDERS
Volume 36, Issue 2, Pages 424-433Publisher
WILEY
DOI: 10.1002/mds.28342
Keywords
Parkinson' s disease; genetics; progression; genome‐ wide association study
Categories
Funding
- Parkinson's UK
- National Institute for Health Research (NIHR) Dementias and Neurodegenerative Diseases Research Network (DeNDRoN)
- NIHR Oxford Biomedical Research Centre based at Oxford University Hospitals NHS Trust and the University of Oxford
- National Institute for Health Research University College London Hospitals Biomedical Research Centre
- Intramural Research Program of the NIH, National Institute on Aging
- RCUK/UKRI Research Innovation Fellowship (Medical Research Council)
- NIHR Cambridge Biomedical Research Centre Dementia and Neurodegeneration theme
- NIHR Biomedical Research Centre
- Cure Parkinson's Trust
- Edmond J. Safra Philanthropic Foundation
- Michael J. Fox Foundation for Parkinson's Research
- MRC [G0700943, MR/M024962/1, MR/N026004/1, MR/S000992/1, MC_EX_MR/N50192X/1] Funding Source: UKRI
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The study found that genetic variants associated with Parkinson's disease risk are not linked to disease progression. The APOE epsilon 4 tagging variant was significantly associated with cognitive progression, while ATP8B2 gene showed a nominal association with motor progression. The new method shows promise in improving the measurement of symptom progression in PD.
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 epsilon 4 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 x 10(-6)). Conclusions We provide early evidence that this new method in PD improves measurement of symptom progression. We show that the APOE epsilon 4 allele drives progressive cognitive impairment in PD. Replication of this method and results in independent cohorts are needed. (c) 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC. on behalf of International Parkinson and Movement Disorder Society
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