Journal
MOVEMENT DISORDERS
Volume 34, Issue 12, Pages 1839-1850Publisher
WILEY
DOI: 10.1002/mds.27845
Keywords
Apolipoprotein E; GBA; genomewide association study; Parkinson's disease
Categories
Funding
- Public Health Service grant from the National Institute of Neurological Disorders and Stroke (NINDS) [NS24778]
- General Clinical Research Centers Program of the National Institutes of Health at Columbia University [RR00645]
- University of Virginia [RR00847]
- University of Pennsylvania [RR00040]
- University of Iowa [RR00059]
- Ohio State University [RR00034]
- Oregon Health Sciences University [RR00334]
- Baylor College of Medicine [RR00350]
- University of California [RR00827]
- Johns Hopkins University [RR00035]
- University of Michigan [RR00042]
- Washington University [RR00036]
- Parkinson's Disease Foundation at Columbia-Presbyterian Medical Center
- National Parkinson Foundation
- Parkinson Foundation of Canada
- United Parkinson Foundation, Chicago
- American Parkinson's Disease Association, New York
- University of Rochester
- Assistance Publique Hopitaux de Paris
- French Ministry of Health (PHRC 2008) [AOM08010]
- Agence Nationale pour la Securite des Medicaments (ANSM 2013)
- Harvard NeuroDiscovery Center
- Massachusetts Alzheimer' Disease Research Center [NIA P50AG005134]
- NINDS [U01NS043128, 5U01NS050095-05, U01NS082157, U01NS100603]
- Research Council of Norway
- South-Eastern Norway Regional Health Authority
- ZonMw (Netherlands Organization for Health Research and Development) [75020012]
- Michael J. Fox Foundation for Parkinson's Research
- Western Norway Regional Health Authority
- Stavanger University Hospital Research Funds
- Norwegian Parkinson's Disease Association
- Cure Parkinson's Trust
- Van Geest Foundation
- National Institute of Health Research Cambridge Biomedical Research Centre
- Department of Defense Neurotoxin Exposure Treatment Parkinson's Research Program [W23RRYX7022N606]
- Parkinson's Disease Foundation
- Lundbeck Pharmaceuticals
- Cephalon Inc
- Lundbeck Inc
- John Blume Foundation
- Smart Family Foundation
- RJG Foundation
- Kinetics Foundation
- Amarin Neuroscience LTD
- CHDI Foundation Inc
- National Institutes of Health (NINDS)
- Columbia Parkinson's Disease Research Center
- Alkemade-Keuls Foundation
- Stichting Parkinson Fonds
- Parkinson Vereniging
- Netherlands Organisation for Health Research and Development
- NINDS
- National Institutes of Health (NHGRI)
- Massachusetts General Hospital [RR01066]
- University of Rochester [RR00044]
- Brown University [RR02038]
- Michael J. Fox Foundation
- VGZ (health insurance company)
- GlaxoSmithKline
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Background Several reports have identified different patterns of Parkinson's disease progression in individuals carrying missense variants in GBA or LRRK2 genes. The overall contribution of genetic factors to the severity and progression of Parkinson's disease, however, has not been well studied. Objectives To test the association between genetic variants and the clinical features of Parkinson's disease on a genomewide scale. Methods We accumulated individual data from 12 longitudinal cohorts in a total of 4093 patients with 22,307 observations for a median of 3.81 years. Genomewide associations were evaluated for 25 cross-sectional and longitudinal phenotypes. Specific variants of interest, including 90 recently identified disease-risk variants, were also investigated post hoc for candidate associations with these phenotypes. Results Two variants were genomewide significant. Rs382940(T>A), within the intron of SLC44A1, was associated with reaching Hoehn and Yahr stage 3 or higher faster (hazard ratio 2.04 [1.58-2.62]; P value = 3.46E-8). Rs61863020(G>A), an intergenic variant and expression quantitative trait loci for alpha-2A adrenergic receptor, was associated with a lower prevalence of insomnia at baseline (odds ratio 0.63 [0.52-0.75]; P value = 4.74E-8). In the targeted analysis, we found 9 associations between known Parkinson's risk variants and more severe motor/cognitive symptoms. Also, we replicated previous reports of GBA coding variants (rs2230288: p.E365K; rs75548401: p.T408M) being associated with greater motor and cognitive decline over time, and an APOE E4 tagging variant (rs429358) being associated with greater cognitive deficits in patients. Conclusions We identified novel genetic factors associated with heterogeneity of Parkinson's disease. The results can be used for validation or hypothesis tests regarding Parkinson's disease. (c) 2019 International Parkinson and Movement Disorder Society
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