Genomewide Association Studies of LRRK2 Modifiers of Parkinson's Disease.
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Lai Dongbing, Alipanahi Babak, Fontanillas Pierre, Schwantes-An Tae-Hwi, Aasly Jan, Alcalay Roy N, Beecham Gary W, Berg Daniela, Bressman Susan, Brice Alexis, Brockman Kathrin, Clark Lorraine, Cookson Mark, Das Sayantan, Van Deerlin Vivianna, Follett Jordan, Farrer Matthew J, Trinh Joanne, Gasser Thomas, Goldwurm Stefano, Gustavsson Emil, Klein Christine, Lang Anthony E, Langston J William, Latourelle Jeanne, Lynch Timothy, Marder Karen, Marras Connie, Martin Eden R, McLean Cory Y, Mejia-Santana Helen, Molho Eric, Myers Richard H, Nuytemans Karen, Ozelius Laurie, Payami Haydeh, Raymond Deborah, Rogaeva Ekaterina, Rogers Michael P, Ross Owen A, Samii Ali, Saunders-Pullman Rachel, Schüle Birgitt, Schulte Claudia, Scott William K, Tanner Caroline, Tolosa Eduardo, Tomkins James E, Vilas Dolores, Trojanowski John Q, 23andMe Research Team, Uitti Ryan, Vance Jeffery M, Visanji Naomi P, Wszolek Zbigniew K, Zabetian Cyrus P, Mirelman Anat, Giladi Nir, Orr Urtreger Avi, Cannon Paul, Fiske Brian, Foroud Tatiana
Аннотация
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.