Journal Article

DZNE-2021-01395

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Genomewide Association Studies of LRRK2 Modifiers of Parkinson's Disease.

Lai, D. ; Alipanahi, B. ; Fontanillas, P. ; Schwantes-An, T.-H. ; Aasly, J. ; Alcalay, R. N. ; Beecham, G. W. ; Berg, D. ; Bressman, S. ; Brice, A. ; Brockmann, K.DZNE* ; Clark, L. ; Cookson, M. ; Das, S. ; Van Deerlin, V. ; Follett, J. ; Farrer, M. J. ; Trinh, J. ; Gasser, T.DZNE* ; Goldwurm, S. ; Gustavsson, E. ; Klein, C. ; Lang, A. E. ; Langston, J. W. ; Latourelle, J. ; Lynch, T. ; Marder, K. ; Marras, C. ; Martin, E. R. ; McLean, C. Y. ; Mejia-Santana, H. ; Molho, E. ; Myers, R. H. ; Nuytemans, K. ; Ozelius, L. ; Payami, H. ; Raymond, D. ; Rogaeva, E. ; Rogers, M. P. ; Ross, O. A. ; Samii, A. ; Saunders-Pullman, R. ; Schüle, B. ; Schulte, C.DZNE* ; Scott, W. K. ; Tanner, C. ; Tolosa, E. ; Tomkins, J. E. ; Vilas, D. ; Trojanowski, J. Q. ; Team, 2. R. (Collaboration Author) ; Uitti, R. ; Vance, J. M. ; Visanji, N. P. ; Wszolek, Z. K. ; Zabetian, C. P. ; Mirelman, A. ; Giladi, N. ; Orr Urtreger, A. ; Cannon, P. ; Fiske, B. ; Foroud, T.

2021
Wiley-Blackwell Hoboken, NJ

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Please use a persistent id in citations: doi:10.1002/ana.26094

Abstract: 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.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.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.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.

Keyword(s): Aged (MeSH) ; Female (MeSH) ; Genetic Predisposition to Disease (MeSH) ; Genome-Wide Association Study (MeSH) ; Genotype (MeSH) ; Humans (MeSH) ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2: genetics (MeSH) ; Male (MeSH) ; Middle Aged (MeSH) ; Mutation (MeSH) ; Parkinson Disease: genetics (MeSH) ; Penetrance (MeSH) ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2

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Contributing Institute(s):

1. Parkinson Genetics (AG Gasser)
2. Parkinson's Disease Genetics (AG Berg)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2021

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; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; DEAL Wiley ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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