Genomewide Association Studies of <scp> <i>LRRK2</i> </scp> Modifiers of Parkinson's Disease
Dongbing Lai, Babak Alipanahi, Pierre Fontanillas, Tae‐Hwi Schwantes‐An, Jan Aasly, Roy N. Alcalay, Gary W. Beecham, Daniela Berg, Susan Bressman, Alexis Brice, Kathrin Brockman, Lorraine N. Clark, Mark Cookson, Sayantan Das, Vivianna M. Van Deerlin, Jordan Follett, Matthew J. Farrer, Joanne Trinh, Thomas Gasser, Stefano Goldwurm, Emil K. Gustavsson, Christine Klein, Anthony E. Lang, J. William Langston, Jeanne C. Latourelle, Timothy Lynch, Karen Marder, Connie Marras, Eden R. Martin, Cory Y. McLean, Helen Mejia‐Santana, Eric Molho, Richard H. Myers, Karen Nuytemans, Laurie J. Ozelius, Haydeh Payami, Deborah Raymond, Ekaterina Rogaeva, Michael P. Rogers, Owen A. Ross, Ali Samii, Rachel Saunders‐Pullman, Birgitt Schüle, Claudia Schulte, William K. Scott, Caroline M. Tanner, Eduardo Tolosa, James E. Tomkins, Dolores Vilas, John Q. Trojanowski, Ryan J. Uitti, Jeffery M. Vance, Naomi P. Visanji, Zbigniew K. Wszołek, Cyrus P. Zabetian, Anat Mirelman, Nir Giladi, Avi Orr Urtreger, P. F. Cannon, Brian Fiske, Tatiana Foroud
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.