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@ARTICLE{Lake:162933,
author = {Lake, Julie and Reed, Xylena and Langston, Rebekah G and
Nalls, Mike A and Gan-Or, Ziv and Cookson, Mark R and
Singleton, Andrew B and Blauwendraat, Cornelis and Leonard,
Hampton L},
collaboration = {Consortium, International Parkinson's Disease Genomics},
title = {{C}oding and {N}oncoding {V}ariation in {LRRK}2 and
{P}arkinson's {D}isease {R}isk.},
journal = {Movement disorders},
volume = {37},
number = {1},
issn = {1531-8257},
address = {New York, NY},
publisher = {Wiley},
reportid = {DZNE-2021-01585},
pages = {95-105},
year = {2022},
note = {(CC BY)},
abstract = {The leucine-rich repeat kinase 2 (LRRK2) gene harbors both
rare highly damaging missense variants (eg, p.G2019S) and
common noncoding variants (eg, rs76904798) with lower effect
sizes that are associated with Parkinson's disease (PD)
risk.This study aimed to investigate in a large
meta-analysis whether the LRRK2 Genome-Wide Association
Study (GWAS) signal represented by rs76904798 is
independently associated with PD risk from LRRK2 coding
variation and whether complex linkage disequilibrium
structures with p.G2019S and the 5' noncoding haplotype
account for the association of LRRK2 coding variants.We
performed a meta-analysis using imputed genotypes from
17,838 patients, 13,404 proxy patients, and 173,639 healthy
controls of European ancestry. We excluded carriers of
p.G2019S and/or rs76904798 to clarify the role of LRRK2
coding variation in mediating disease risk and excluded
carriers of relatively rare LRRK2 coding variants to assess
the independence of rs76904798. We also investigated the
co-inheritance of LRRK2 coding variants with p.G2019S,
rs76904798, and p.N2081D.LRRK2 rs76904798 remained
significantly associated with PD after excluding the
carriers of relatively rare LRRK2 coding variants. LRRK2
p.R1514Q and p.N2081D were frequently co-inherited with
rs76904798, and the allele distribution of p.S1647T
significantly changed among patients after removing
rs76904798 carriers.These data suggest that the LRRK2 coding
variants previously related to PD (p.N551K, p.R1398H,
p.M1646T, and p.N2081D) do not drive the 5' noncoding GWAS
signal. These data, however, do not preclude the independent
association of the haplotype p.N551K-p.R1398H and p.M1646T
with altered disease risk. © 2021 The Authors. Movement
Disorders published by Wiley Periodicals LLC on behalf of
International Parkinson Movement Disorder Society. This
article has been contributed to by US Government employees
and their work is in the public domain in the USA.},
keywords = {Genome-Wide Association Study / Genotype / Haplotypes:
genetics / Humans / Leucine-Rich Repeat Serine-Threonine
Protein Kinase-2: genetics / Mutation / Parkinson Disease:
genetics / LRRK2 (Other) / Parkinson's disease (Other) /
association (Other) / genetics (Other)},
cin = {Tübingen common / AG Gasser},
ddc = {610},
cid = {I:(DE-2719)6000018 / I:(DE-2719)1210000},
pnm = {353 - Clinical and Health Care Research (POF4-353)},
pid = {G:(DE-HGF)POF4-353},
typ = {PUB:(DE-HGF)16},
pmc = {pmc:PMC9292230},
pubmed = {pmid:34542912},
doi = {10.1002/mds.28787},
url = {https://pub.dzne.de/record/162933},
}