Copy Number Variation and Haplotype Analysis of 17q21.31 Reveals Increased Risk Associated with Progressive Supranuclear Palsy and Gene Expression Changes in Neuronal Cells.

IF 7.4 1区医学 Q1 CLINICAL NEUROLOGY Movement Disorders Pub Date : 2025-03-08 DOI:10.1002/mds.30150

Hui Wang, Timothy S Chang, Beth A Dombroski, Po-Liang Cheng, Ya-Qin Si, Albert Tucci, Vishakha Patil, Leopoldo Valiente-Banuet, Chong Li, Kurt Farrell, Catriona Mclean, Laura Molina-Porcel, Alex Rajput, Peter Paul De Deyn, Nathalie Le Bastard, Marla Gearing, Laura Donker Kaat, John C Van Swieten, Elise Dopper, Bernardino F Ghetti, Kathy L Newell, Claire Troakes, Justo G de Yébenes, Alberto Rábano-Gutierrez, Tina Meller, Wolfgang H Oertel, Gesine Respondek, Maria Stamelou, Thomas Arzberger, Sigrun Roeber, Ulrich Müller, Franziska Hopfner, Pau Pastor, Alexis Brice, Alexandra Durr, Isabelle Le Ber, Thomas G Beach, Geidy E Serrano, Lili-Naz Hazrati, Irene Litvan, Rosa Rademakers, Owen A Ross, Douglas Galasko, Adam L Boxer, Bruce L Miller, Willian W Seeley, Vivianna M Van Deerlin, Edward B Lee, Charles L White, Huw R Morris, Rohan de Silva, John F Crary, Alison M Goate, Jeffrey S Friedman, Yaroslau Compta, Yuk Yee Leung, Giovanni Coppola, Adam C Naj, Li-San Wang, Clifton Dalgard, Dennis W Dickson, Günter U Höglinger, Jung-Ying Tzeng, Daniel H Geschwind, Gerard D Schellenberg, Wan-Ping Lee

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引用次数: 0

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.

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来源期刊

Movement Disorders 医学-临床神经学

CiteScore

13.30

自引率

8.10%

发文量

371

审稿时长

12 months

期刊介绍： Movement Disorders publishes a variety of content types including Reviews, Viewpoints, Full Length Articles, Historical Reports, Brief Reports, and Letters. The journal considers original manuscripts on topics related to the diagnosis, therapeutics, pharmacology, biochemistry, physiology, etiology, genetics, and epidemiology of movement disorders. Appropriate topics include Parkinsonism, Chorea, Tremors, Dystonia, Myoclonus, Tics, Tardive Dyskinesia, Spasticity, and Ataxia.