全基因组测序分析揭示与进行性核上性麻痹相关的新易感基因座和结构变异。

Whole-Genome Sequencing Analysis Reveals New Susceptibility Loci and Structural Variants Associated with Progressive Supranuclear Palsy.

作者信息

Wang Hui, Chang Timothy S, Dombroski Beth A, Cheng Po-Liang, Patil Vishakha, Valiente-Banuet Leopoldo, Farrell Kurt, Mclean Catriona, Molina-Porcel Laura, Rajput Alex, De Deyn Peter Paul, Bastard Nathalie Le, Gearing Marla, Kaat Laura Donker, Swieten John C Van, Dopper Elise, Ghetti Bernardino F, Newell Kathy L, Troakes Claire, de Yébenes Justo G, Rábano-Gutierrez Alberto, Meller Tina, Oertel Wolfgang H, Respondek Gesine, Stamelou Maria, Arzberger Thomas, Roeber Sigrun, Müller Ulrich, Hopfner Franziska, Pastor Pau, Brice Alexis, Durr Alexandra, Ber Isabelle Le, 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, Deerlin Vivanna M Van, Lee Edward B, White Charles L, Morris Huw, de Silva Rohan, Crary John F, Goate Alison M, Friedman Jeffrey S, Leung Yuk Yee, Coppola Giovanni, Naj Adam C, Wang Li-San, Dickson Dennis W, Höglinger Günter U, Schellenberg Gerard D, Geschwind Daniel H, Lee Wan-Ping

机构信息

Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

出版信息

medRxiv. 2024 Jan 30:2023.12.28.23300612. doi: 10.1101/2023.12.28.23300612.

DOI:10.1101/2023.12.28.23300612

PMID:38234807

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10793533/

Abstract

BACKGROUND

Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs).

METHOD

In this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed.

RESULTS

Our analysis of common SNVs and indels confirmed known genetic loci at , , S, , , and , and further uncovered novel signals in , . Notably, in contrast to Alzheimer's disease (AD), we observed the ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including , , , and . In the H1/H2 haplotype region, there is a burden of rare deletions and duplications ( = 6.73×10) in PSP.

CONCLUSIONS

Through WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.

摘要

背景

进行性核上性麻痹（PSP）是一种罕见的神经退行性疾病，其特征是tau蛋白在星形胶质细胞、神经元和少突胶质细胞中聚集。先前针对PSP的全基因组关联研究基于基因型阵列，因此，对于分析罕见变异以及较大的突变，如小插入/缺失（indels）和结构变异（SVs）而言并不充分。

方法

在本研究中，我们对1718例欧洲血统的病例和2944例对照进行了全基因组测序（WGS），并对单核苷酸变异（SNVs）、indels和SVs进行了关联分析。在1718例PSP个体中，1441例经尸检确诊，277例为临床诊断。

结果

我们对常见SNVs和indels的分析证实了已知的基因座位于……，并在……中进一步发现了新的信号。值得注意的是，与阿尔茨海默病（AD）不同，我们观察到ε2等位基因在PSP中是风险等位基因。对罕见SNVs和indels的分析确定了……中的显著关联，进一步的基因网络分析确定了PSP中失调的一个神经元基因模块。此外，在H1/H2单倍型区域（17q21.31）和其他基因座，包括……，观察到7个与PSP相关的常见SVs。在H1/H2单倍型区域，PSP中存在罕见缺失和重复的负担（=6.73×10）。