Wang, Hui;
Chang, Timothy S;
Dombroski, Beth A;
Cheng, Po-Liang;
Si, Ya-Qin;
Tucci, Albert;
Patil, Vishakha;
... PSP, Genetics Study Grp; + view all
(2025)
Copy Number Variation and Haplotype Analysis of 17q21.31 Reveals Increased Risk Associated with Progressive Supranuclear Palsy and Gene Expression Changes in Neuronal Cells.
Movement Disorders
, 40
(5)
pp. 950-961.
10.1002/mds.30150.
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Movement Disorders - 2025 - Wang - Copy Number Variation and Haplotype Analysis of 17q21 31 Reveals Increased Risk.pdf - Published Version Download (1MB) | Preview |
Abstract
Background: 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). // Objective: To investigate the association between CNVs and structural forms on 17q.21.31 with the risk of PSP. // Methods: 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. // Results: 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. // Conclusions: 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.
| Type: | Article |
|---|---|
| Title: | Copy Number Variation and Haplotype Analysis of 17q21.31 Reveals Increased Risk Associated with Progressive Supranuclear Palsy and Gene Expression Changes in Neuronal Cells |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1002/mds.30150 |
| Publisher version: | https://doi.org/10.1002/mds.30150 |
| Language: | English |
| Additional information: | Copyright © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, https://creativecommons.org/licenses/by-nc-nd/4.0/, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. |
| Keywords: | Progressive supranuclear palsy; H1 and H2 haplotypes; 17q21.31; copy number variations; single-cell gene expression |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10208678 |
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