1. Genomewide Association Studies of LRRK2 Modifiers of Parkinson's Disease
- Author
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Paul Cannon, Laurie J. Ozelius, James E. Tomkins, Nir Giladi, Owen A. Ross, Emil K. Gustavsson, Avi Orr Urtreger, Ali Samii, Tae-Hwi Schwantes-An, Sayantan Das, Haydeh Payami, Claudia Schulte, Eduardo Tolosa, Timothy Lynch, Eden R. Martin, Matthew J. Farrer, Brian K. Fiske, Pierre Fontanillas, Eric Molho, Ryan J. Uitti, Babak Alipanahi, Dolores Vilas, Jan O. Aasly, Dongbing Lai, Richard H. Myers, William K. Scott, Gary W. Beecham, Jordan Follett, Thomas Gasser, John Q. Trojanowski, Zbigniew K. Wszolek, Jeanne C. Latourelle, Caroline M. Tanner, Joanne Trinh, Alexis Brice, Lorraine N. Clark, Roy N. Alcalay, Karen Marder, Susan Bressman, Deborah Raymond, Tatiana Foroud, Connie Marras, Kathrin Brockman, Birgitt Schüle, Cory Y. McLean, Rachel Saunders-Pullman, Ekaterina Rogaeva, Daniela Berg, Cyrus P. Zabetian, Stefano Goldwurm, Karen Nuytemans, Mark R. Cookson, Helen Mejia-Santana, Jeffery M. Vance, Christine Klein, Naomi P. Visanji, J. William Langston, Michael P. Rogers, Anthony E. Lang, Anat Mirelman, Vivianna M. Van Deerlin, Lai, Dongbing [0000-0001-7803-580X], Brockman, Kathrin [0000-0002-7515-8596], Klein, Christine [0000-0003-2102-3431], Ross, Owen A [0000-0003-4813-756X], Visanji, Naomi P [0000-0001-5968-7845], Zabetian, Cyrus P [0000-0002-7739-4306], Mirelman, Anat [0000-0002-1520-2292], and Apollo - University of Cambridge Repository
- Subjects
0301 basic medicine ,Male ,Aging ,Parkinson's disease ,Penetrance ,Disease ,Neurodegenerative ,medicine.disease_cause ,0302 clinical medicine ,genetics [Parkinson Disease] ,2.1 Biological and endogenous factors ,Aetiology ,Research Articles ,Genetics ,Mutation ,Parkinson's Disease ,Parkinson Disease ,Middle Aged ,LRRK2 ,Neurology ,Neurological ,Female ,Research Article ,Genotype ,Clinical Sciences ,Biology ,Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 ,23andMe Research Team ,03 medical and health sciences ,medicine ,Humans ,Genetic Predisposition to Disease ,ddc:610 ,Chromosome 12 ,Aged ,Linkage (software) ,Neurology & Neurosurgery ,Prevention ,Human Genome ,Neurosciences ,medicine.disease ,nervous system diseases ,Brain Disorders ,030104 developmental biology ,Chromosome 3 ,genetics [Leucine-Rich Repeat Serine-Threonine Protein Kinase-2] ,Neurology (clinical) ,030217 neurology & neurosurgery ,Genome-Wide Association Study - 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 genome-wide 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 genome-wide 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 genome-wide significance for the penetrance model. Co-immunoprecipitation analyses of LRRK2 and CORO1C supported an interaction between these two 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. This article is protected by copyright. All rights reserved.
- Published
- 2021