Journal
ANNALS OF NEUROLOGY
Volume 90, Issue 1, Pages 76-88Publisher
WILEY
DOI: 10.1002/ana.26094
Keywords
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Categories
Funding
- National Institutes of Health [HHSN268201200008I, AG010124, AG062418, K02NS080915, NS036630, NS053488, NS071674, P50NS039764, P50NS062684, P50NS072187, R01NS 065070, R01NS078086, R01NS096740, U54NS100693, U54NS110435, UL1TR000040, UL1TR001873]
- Michael J. Fox Foundation for Parkinson's Research [7984, 7984.01, 7984.02, 8981]
- Albertson Parkinson's Research Foundation
- Brookdale Foundation
- Else Kroener Fresenius Foundation
- Haworth Family Professorship in Neurodegenerative Diseases fund
- Little Family Foundation
- Parkinson's Foundation
- Sol Goldman Charitable Trust
- Department of Veterans Affairs [5I01CX001702]
- DOD [W81XWH-17-1-0249]
- DFG [FOR2488]
- Canadian Consortium on Neurodegeneration in Aging
- Canadian Institutes of Health Research
- 2019 Biomarkers Across Neurodegenerative Diseases Grant Program
- BAND3 [18063]
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This study identified a variant in the intronic region of CORO1C that may modify the penetrance of LRRK2 mutations, and common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations.
Objective The aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease. Methods We performed the first genomewide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age-at-onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genomewide association study of Parkinson's disease was able to explain variability in penetrance and age-at-onset in LRRK2 mutation carriers. Results A variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; p value = 2.5E-08, beta = 1.27, SE = 0.23, risk allele: C) met genomewide significance for the penetrance model. Co-immunoprecipitation analyses of LRRK2 and CORO1C supported an interaction between these 2 proteins. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: p value = 1.1E-07; age-at-onset top variant: p value = 9.3E-07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age-at-onset. Interpretation This study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations. ANN NEUROL 2021
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