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@ARTICLE{Wang:271349,
author = {Wang, Hui and Chang, Timothy S and Dombroski, Beth A and
Cheng, Po-Liang and Patil, Vishakha and Valiente-Banuet,
Leopoldo and Farrell, Kurt and Mclean, Catriona and
Molina-Porcel, Laura and Rajput, Alex and De Deyn, Peter
Paul and Le Bastard, Nathalie and Gearing, Marla and Kaat,
Laura Donker and Van Swieten, John C and Dopper, Elise and
Ghetti, Bernardino F and Newell, Kathy L and Troakes, Claire
and de Yébenes, Justo G and Rábano-Gutierrez, Alberto and
Meller, Tina and Oertel, Wolfgang H and Respondek, Gesine
and Stamelou, Maria and Arzberger, Thomas and Roeber, Sigrun
and Müller, Ulrich and Hopfner, Franziska and Pastor, Pau
and Brice, Alexis and Durr, Alexandra and Le Ber, Isabelle
and Beach, Thomas G and Serrano, Geidy E and Hazrati,
Lili-Naz and Litvan, Irene and Rademakers, Rosa and Ross,
Owen A and Galasko, Douglas and Boxer, Adam L and Miller,
Bruce L and Seeley, Willian W and Van Deerlin, Vivanna M and
Lee, Edward B and White, Charles L and Morris, Huw and de
Silva, Rohan and Crary, John F and Goate, Alison M and
Friedman, Jeffrey S and Leung, Yuk Yee and Coppola, Giovanni
and Naj, Adam C and Wang, Li-San and Dalgard, Clifton and
Dickson, Dennis W and Höglinger, Günter U and
Schellenberg, Gerard D and Geschwind, Daniel H and Lee,
Wan-Ping},
collaboration = {genetics study group, P. S. P.},
title = {{W}hole-genome sequencing analysis reveals new
susceptibility loci and structural variants associated with
progressive supranuclear palsy.},
journal = {Molecular neurodegeneration},
volume = {19},
number = {1},
issn = {1750-1326},
address = {London},
publisher = {Biomed Central},
reportid = {DZNE-2024-01050},
pages = {61},
year = {2024},
abstract = {Progressive supranuclear palsy (PSP) is a rare
neurodegenerative disease characterized by the accumulation
of aggregated tau proteins in astrocytes, neurons, and
oligodendrocytes. Previous genome-wide association studies
for PSP were based on genotype array, therefore, were
inadequate for the analysis of rare variants as well as
larger mutations, such as small insertions/deletions
(indels) and structural variants (SVs).In this study, we
performed whole genome sequencing (WGS) and conducted
association analysis for single nucleotide variants (SNVs),
indels, and SVs, in a cohort of 1,718 cases and 2,944
controls of European ancestry. Of the 1,718 PSP individuals,
1,441 were autopsy-confirmed and 277 were clinically
diagnosed.Our analysis of common SNVs and indels confirmed
known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and
SP1, and further uncovered novel signals in APOE,
FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in
contrast to Alzheimer's disease (AD), we observed the APOE
ε2 allele to be the risk allele in PSP. Analysis of rare
SNVs and indels identified significant association in ZNF592
and further gene network analysis identified a module of
neuronal genes dysregulated in PSP. Moreover, seven common
SVs associated with PSP were observed in the H1/H2 haplotype
region (17q21.31) and other loci, including IGH, PCMT1,
CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a
burden of rare deletions and duplications (P = 6.73 × 10-3)
in PSP.Through WGS, we significantly enhanced our
understanding of the genetic basis of PSP, providing new
targets for exploring disease mechanisms and therapeutic
interventions.},
keywords = {Humans / Supranuclear Palsy, Progressive: genetics /
Genetic Predisposition to Disease: genetics / Whole Genome
Sequencing / Male / Genome-Wide Association Study / Female /
Aged / Polymorphism, Single Nucleotide: genetics / Middle
Aged / Aged, 80 and over / Apolipoprotein E (APOE) (Other) /
Genome-Wide Association Study (GWAS) (Other) / Progressive
Supranuclear Palsy (PSP) (Other) / Structural Variants (SVs)
(Other) / Whole-Genome Sequencing (WGS) (Other)},
cin = {AG Höglinger ; AG Höglinger / Clinical Research (Munich)},
ddc = {570},
cid = {I:(DE-2719)1110002 / I:(DE-2719)1111015},
pnm = {353 - Clinical and Health Care Research (POF4-353)},
pid = {G:(DE-HGF)POF4-353},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:39152475},
pmc = {pmc:PMC11330058},
doi = {10.1186/s13024-024-00747-3},
url = {https://pub.dzne.de/record/271349},
}