17q21.31基因拷贝数变异和单倍型分析揭示进行性核上性麻痹风险增加和神经元细胞基因表达变化

IF 7.4 1区医学 Q1 CLINICAL NEUROLOGY

Movement Disorders Pub Date : 2025-03-08 DOI:10.1002/mds.30150

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

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Ross PhD, Douglas Galasko MD, Adam L. Boxer MD, PhD, Bruce L. Miller MD, Willian W. Seeley MD, Vivianna M. Van Deerlin MD, PhD, Edward B. Lee MD, PhD, Charles L. White III MD, Huw R. Morris MD, PhD, Rohan de Silva PhD, John F. Crary MD, PhD, Alison M. Goate PhD, Jeffrey S. Friedman MD, PhD, Yaroslau Compta MD, PhD, Yuk Yee Leung PhD, Giovanni Coppola MD, Adam C. Naj PhD, Li-San Wang PhD, PSP Genetics Study Group, Clifton Dalgard PhD, Dennis W. Dickson MD, Günter U. Höglinger MD, Jung-Ying Tzeng PhD, Daniel H. Geschwind MD, PhD, Gerard D. 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引用次数: 0

摘要

背景：以H1/H2单倍型和三个大拷贝数变异（CNVs）为特征的结构形式多样的17q21.31区域是进行性核上性麻痹（PSP）的最强危险位点。目的：探讨CNVs和17q21 .31的结构形式与PSP发病风险的关系。方法：利用1684例PSP病例和2392例对照的全基因组测序数据，鉴定出17q21.31内的3个大CNVs （α、β和γ）及其结构形式，并分析其与PSP的相关性。结果：我们发现γ拷贝数与PSP风险增加相关（比值比[OR] = 1.10, P = 0.0018）。从H1β1γ1 （OR = 1.21）和H1β2γ1 （OR = 1.24）到H1β1γ4 (OR = 1.57)，具有额外γ拷贝的H1结构形式显示出更高的PSP风险。H1c亚型单倍型的风险频率从拥有两个γ拷贝的个体的1%上升到拥有八个γ拷贝的个体的88%。此外，γ重复上调ARL17B、LRRC37A/LRRC37A2和NSFP1的表达，下调KANSL1的表达。背外侧前额皮质单核rna序列分析显示，γ重复主要上调神经元细胞中的LRRC37A/LRRC37A2。结论：调整H1/H2后，γ拷贝数与PSP风险相关，提示17q21.31位点的复杂结构是评估PSP遗传风险的重要考虑因素。©2025作者。Wiley期刊有限责任公司代表国际帕金森和运动障碍学会出版的《运动障碍》。

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

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.