TY  - JOUR
AU  - Lai, Dongbing
AU  - Alipanahi, Babak
AU  - Fontanillas, Pierre
AU  - Schwantes-An, Tae-Hwi
AU  - Aasly, Jan
AU  - Alcalay, Roy N
AU  - Beecham, Gary W
AU  - Berg, Daniela
AU  - Bressman, Susan
AU  - Brice, Alexis
AU  - Brockmann, Kathrin
AU  - Clark, Lorraine
AU  - Cookson, Mark
AU  - Das, Sayantan
AU  - Van Deerlin, Vivianna
AU  - Follett, Jordan
AU  - Farrer, Matthew J
AU  - Trinh, Joanne
AU  - Gasser, Thomas
AU  - Goldwurm, Stefano
AU  - Gustavsson, Emil
AU  - Klein, Christine
AU  - Lang, Anthony E
AU  - Langston, J William
AU  - Latourelle, Jeanne
AU  - Lynch, Timothy
AU  - Marder, Karen
AU  - Marras, Connie
AU  - Martin, Eden R
AU  - McLean, Cory Y
AU  - Mejia-Santana, Helen
AU  - Molho, Eric
AU  - Myers, Richard H
AU  - Nuytemans, Karen
AU  - Ozelius, Laurie
AU  - Payami, Haydeh
AU  - Raymond, Deborah
AU  - Rogaeva, Ekaterina
AU  - Rogers, Michael P
AU  - Ross, Owen A
AU  - Samii, Ali
AU  - Saunders-Pullman, Rachel
AU  - Schüle, Birgitt
AU  - Schulte, Claudia
AU  - Scott, William K
AU  - Tanner, Caroline
AU  - Tolosa, Eduardo
AU  - Tomkins, James E
AU  - Vilas, Dolores
AU  - Trojanowski, John Q
AU  - Uitti, Ryan
AU  - Vance, Jeffery M
AU  - Visanji, Naomi P
AU  - Wszolek, Zbigniew K
AU  - Zabetian, Cyrus P
AU  - Mirelman, Anat
AU  - Giladi, Nir
AU  - Orr Urtreger, Avi
AU  - Cannon, Paul
AU  - Fiske, Brian
AU  - Foroud, Tatiana
TI  - Genomewide Association Studies of LRRK2 Modifiers of Parkinson's Disease.
JO  - Annals of neurology
VL  - 90
IS  - 1
SN  - 1531-8249
CY  - Hoboken, NJ
PB  - Wiley-Blackwell
M1  - DZNE-2021-01395
SP  - 76 - 88
PY  - 2021
AB  - 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.
KW  - Aged
KW  - Female
KW  - Genetic Predisposition to Disease
KW  - Genome-Wide Association Study
KW  - Genotype
KW  - Humans
KW  - Leucine-Rich Repeat Serine-Threonine Protein Kinase-2: genetics
KW  - Male
KW  - Middle Aged
KW  - Mutation
KW  - Parkinson Disease: genetics
KW  - Penetrance
KW  - Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:33938021
C2  - pmc:PMC8252519
DO  - DOI:10.1002/ana.26094
UR  - https://pub.dzne.de/record/162738
ER  -