Abstract
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;90:82–94.
| Original language | English |
|---|---|
| Journal | Annals of Neurology |
| Volume | 90 |
| Issue number | 1 |
| Pages (from-to) | 76-88 |
| Number of pages | 13 |
| ISSN | 0364-5134 |
| DOIs | |
| Publication status | Published - 07.2021 |
Funding
The authors thank the research participants from all sites who made this study possible and Tara Candido for collecting the data. Members of the 23andMe Research Team are: Michelle Agee, Adam Auton, Robert K. Bell, Katarzyna Bryc, Sarah L. Elson, Nicholas A. Furlotte, David A. Hinds, Karen E. Huber, Aaron Kleinman, Nadia K. Litterman, Matthew H. McIntyre, Joanna L. Mountain, Elizabeth S. Noblin, Carrie A.M. Northover, Steven J. Pitts, J. Fah Sathirapongsasuti, Olga V. Sazonova, Janie F. Shelton, Suyash Shringarpure, Chao Tian, Joyce Y. Tung, Vladimir Vacic, and Catherine H. Wilson. Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268201200008I. The authors acknowledge the Indiana University Pervasive Technology Institute for providing [HPC (Big Red II, Karst, Carbonate)] visualization, database, storage, or consulting resources that have contributed to the research results reported within this paper. pEGFP-C1 and pEGFP-CORO1C53 were kind gifts from Prof. Dr. Brunhilde Wirth (University of Cologne; Germany). The 3xFlag-LRRK2 is as described.64 This work is supported by The Michael J. Fox Foundation for Parkinson's Research Grants 7984, 7984.01, 7984.02, and 8981; The Albertson Parkinson's Research Foundation; The Brookdale Foundation; The Else Kroener Fresenius Foundation; The Haworth Family Professorship in Neurodegenerative Diseases fund; The Little Family Foundation; The Parkinson's Foundation; The Sol Goldman Charitable Trust; NIH AG010124, AG062418, K02NS080915, NS036630, NS053488, NS071674, P50NS039764, P50NS062684, P50NS072187, R01NS065070, R01NS078086, R01NS096740, U54NS100693, U54NS110435, UL1TR000040, and UL1TR001873; The Department of Veterans Affairs 5I01CX001702; DOD W81XWH-17-1-0249; The DFG FOR2488; The Canadian Consortium on Neurodegeneration in Aging; The Canadian Institutes of Health Research; The 2019 Biomarkers Across Neurodegenerative Diseases Grant Program; BAND3 18063. Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268201200008I. This work is supported by The Michael J. Fox Foundation for Parkinson's Research Grants 7984, 7984.01, 7984.02, and 8981; The Albertson Parkinson's Research Foundation; The Brookdale Foundation; The Else Kroener Fresenius Foundation; The Haworth Family Professorship in Neurodegenerative Diseases fund; The Little Family Foundation; The Parkinson's Foundation; The Sol Goldman Charitable Trust; NIH AG010124, AG062418, K02NS080915, NS036630, NS053488, NS071674, P50NS039764, P50NS062684, P50NS072187, R01NS065070, R01NS078086, R01NS096740, U54NS100693, U54NS110435, UL1TR000040, and UL1TR001873; The Department of Veterans Affairs 5I01CX001702; DOD W81XWH‐17‐1‐0249; The DFG FOR2488; The Canadian Consortium on Neurodegeneration in Aging; The Canadian Institutes of Health Research; The 2019 Biomarkers Across Neurodegenerative Diseases Grant Program; BAND3 18063.
Research Areas and Centers
- Research Area: Medical Genetics
DFG Research Classification Scheme
- 2.23-02 Molecular Biology and Physiology of Nerve and Glial Cells
