| 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 |
| Authors: |
Wang, Hui; Chang, Timothy S.; Dombroski, Beth A.; Cheng, Po-Liang; Si, Ya-Qin; Tucci, Albert; Patil, Vishakha; Valiente-Banuet, Leopoldo; Li, Chong; Farrell, Kurt; Mclean, Catriona; Molina-Porcel, Laura; Rajput, Alex; De Deyn, Peter Paul; Le Bastard, Nathalie; Gearing, Marla; Kaat, Laura Donker; Van Swieten, John C.; Dopper, Elise; Ghetti, Bernardino F.; Newell, Kathy L.; Troakes, Claire; de Yebenes, Justo G.; Rabano-Gutierrez, Alberto; Meller, Tina; Oertel, Wolfgang H.; Respondek, Gesine; Stamelou, Maria; Arzberger, Thomas; Roeber, Sigrun; Mueller, Ulrich; Hopfner, Franziska; Pastor, Pau; Brice, Alexis; Durr, Alexandra; Le Ber, Isabelle; Beach, Thomas G.; Serrano, Geidy E.; Hazrati, Lili-Naz; Litvan, Irene; Rademakers, Rosa; Ross, Owen A.; Galasko, Douglas; Boxer, Adam L.; Miller, Bruce L.; Seeley, Willian W.; Van Deerlin, Vivianna M.; Lee, Edward B.; White, Charles L.; Morris, Huw R.; de Silva, Rohan; Crary, John F.; Goate, Alison M.; Friedman, Jeffrey S.; Compta, Yaroslau; Leung, Yuk Yee; Coppola, Giovanni; Naj, Adam C.; Wang, Li-San; Dalgard, Clifton; Dickson, Dennis W.; Hoeglinger, Guenter U.; Tzeng, Jung-Ying; Geschwind, Daniel H.; Schellenberg, Gerard D.; Lee, Wan-Ping |
| Contributors: |
PSP Genetics Study Group |
| Source: |
0885-3185 ; Movement disorders: video, videotape supplements |
| Publication Year: |
2025 |
| Collection: |
IRUA - Institutional Repository van de Universiteit Antwerpen |
| Subject Terms: |
Human medicine |
| Description: |
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 (alpha, beta, and gamma) and structural forms within 17q21.31 were identified and analyzed for their association with PSP. Results: We found that the copy number of gamma was associated with increased PSP risk (odds ratio [OR] = 1.10, P = 0.0018). From H1 beta 1 gamma 1 (OR = 1.21) and H1 beta 2 gamma 1 (OR = 1.24) to H1 beta 1 gamma 4 (OR = 1.57), structural forms of H1 with additional copies of gamma displayed a higher risk for PSP. The frequency of the risk sub-haplotype H1c rises from 1% in individuals with two gamma copies to 88% in those with eight copies. Additionally, gamma 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 gamma duplication primarily up-regulates LRRC37A/LRRC37A2 in neuronal cells. Conclusions: The copy number of gamma 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. (c) 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/isi/001439786800001 |
| Availability: |
https://hdl.handle.net/10067/2133330151162165141; https://repository.uantwerpen.be/docstore/d:irua:28138 |
| Rights: |
info:eu-repo/semantics/openAccess |
| Accession Number: |
edsbas.8A507A6D |
| Database: |
BASE |