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@ARTICLE{Wang:278787,
author = {Wang, Hui and Chang, Timothy S and Dombroski, Beth A and
Cheng, Po-Liang and Si, Ya-Qin and Tucci, Albert and Patil,
Vishakha and Valiente-Banuet, Leopoldo and Li, Chong 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 Donker Kaat, Laura 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, Vivianna M and Lee, Edward B and White, Charles
L and Morris, Huw R and de Silva, Rohan and Crary, John F
and Goate, Alison M and Friedman, Jeffrey S and Compta,
Yaroslau 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 Tzeng, Jung-Ying and
Geschwind, Daniel H and Schellenberg, Gerard D and Lee,
Wan-Ping},
collaboration = {Group, PSP Genetics Study},
othercontributors = {Lang, Anthony E and Grossman, Murray and Knopman, David S
and Schneider, Lon S and Doody, Rachelle S and Lees, Andrew
and Golbe, Lawrence I and Williams, David R and Corvol,
Jean-Cristophe and Ludolph, Albert and Burn, David and
Lorenzl, Stefan and Roberson, Erik D and Koestler, Mary and
Jack, Clifford R and Randolph, Christopher and Lobach, Iryna
V and Heuer, Hilary W and Gozes, Illana and Parker, Lesley
and Whitaker, Steve and Hirman, Joe and Stewart, Alistair J
and Gold, Michael and Morimoto, Bruce H and Herms, Jochen
and Gelpi, Ellen},
title = {{C}opy {N}umber {V}ariation and {H}aplotype {A}nalysis of
17q21.31 {R}eveals {I}ncreased {R}isk {A}ssociated with
{P}rogressive {S}upranuclear {P}alsy and {G}ene {E}xpression
{C}hanges in {N}euronal {C}ells.},
journal = {Movement disorders},
volume = {40},
number = {5},
issn = {0885-3185},
address = {New York, NY},
publisher = {Wiley},
reportid = {DZNE-2025-00623},
pages = {950 - 961},
year = {2025},
abstract = {The 17q21.31 region with various structural forms
characterized by the H1/H2 haplotypes and three large copy
number variations (CNVs) represents the strongest risk locus
in progressive supranuclear palsy (PSP).To investigate the
association between CNVs and structural forms on 17q.21.31
with the risk of PSP.Utilizing whole genome sequencing data
from 1684 PSP cases and 2392 controls, the three large CNVs
(α, β, and γ) and structural forms within 17q21.31 were
identified and analyzed for their association with PSP.We
found that the copy number of γ was associated with
increased PSP risk (odds ratio [OR] = 1.10, P = 0.0018).
From H1β1γ1 (OR = 1.21) and H1β2γ1 (OR = 1.24) to
H1β1γ4 (OR = 1.57), structural forms of H1 with additional
copies of γ displayed a higher risk for PSP. The frequency
of the risk sub-haplotype H1c rises from $1\%$ in
individuals with two γ copies to $88\%$ in those with eight
copies. Additionally, γ duplication up-regulates expression
of ARL17B, LRRC37A/LRRC37A2, and NSFP1, while
down-regulating KANSL1. Single-nucleus RNA-seq of the
dorsolateral prefrontal cortex analysis reveals γ
duplication primarily up-regulates LRRC37A/LRRC37A2 in
neuronal cells.The copy number of γ is associated with the
risk of PSP after adjusting for H1/H2, indicating that the
complex structure at 17q21.31 is an important consideration
when evaluating the genetic risk of PSP. © 2025 The
Author(s). Movement Disorders published by Wiley Periodicals
LLC on behalf of International Parkinson and Movement
Disorder Society.},
keywords = {Humans / Supranuclear Palsy, Progressive: genetics / DNA
Copy Number Variations: genetics / Female / Male /
Chromosomes, Human, Pair 17: genetics / Aged / Haplotypes:
genetics / Neurons: metabolism / Genetic Predisposition to
Disease: genetics / Middle Aged / Gene Expression / 17q21.31
(Other) / H1 and H2 haplotypes (Other) / copy number
variations (Other) / progressive supranuclear palsy (Other)
/ single‐cell gene expression (Other)},
cin = {Clinical Research (Munich)},
ddc = {610},
cid = {I:(DE-2719)1111015},
pnm = {353 - Clinical and Health Care Research (POF4-353)},
pid = {G:(DE-HGF)POF4-353},
typ = {PUB:(DE-HGF)16},
pmc = {pmc:PMC12089919},
pubmed = {pmid:40055946},
doi = {10.1002/mds.30150},
url = {https://pub.dzne.de/record/278787},
}