Novel approaches to identify tandem repeat expansions in neurodegenerative disease

识别神经退行性疾病串联重复扩增的新方法

• 批准号: 10593996
• 负责人: Paul Nils Valdmanis
• 金额: $ 38.88万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10593996
• 关键词: African American; Age; Alzheimer' s Disease; Alzheimer' s disease risk; Amyotrophic Lateral Sclerosis; Back; Base Sequence; Biological Models; Biology; Cells; Complement; DNA; Data; Data Set; Dementia; Disease; Ethnic Population; General Population; Genes; Genetic; Genetic Risk; Genome; Goals; Haplotypes; Heterozygote; Hispanic; Human; Human Genome; Individual; Introns; Lead; Length; Maps; Methods; Minisatellite Repeats; Molecular; NID gene; Neurodegenerative Disorders; Not Hispanic or Latino; Nucleic Acid Regulatory Sequences; Nucleotides; Outcome; Pathogenesis; Pathogenicity; Patients; Play; Population; Positioning Attribute; Property; Qualifying; RNA-Binding Proteins; Reporting; Role; Sampling; Site; Structure; Tandem Repeat Sequences; Techniques; Technology; Testing; Validation; Variant; WD Repeat; Work; causal variant; cohort; experimental study; genome wide association study; genome-wide; global health; insight; multi-ethnic; multiple omics; nervous system disorder; neurogenetics; novel; novel strategies; novel therapeutics; promoter; risk variant; sex; whole genome

Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases and has a high global health burden. While several AD genetic risk loci have been identified, the causal variant at these genome- wide association study (GWAS) sites is still unknown despite intensive sequencing efforts. Importantly, however, most genome-wide sequencing methods fail to accurately resolve tandem repeats, over 40 of which are key drivers of neurological disorders. We hypothesize that a substantial fraction of genetic contributions to AD come from variable number tandem repeats (VNTRs) that often contain internal repeat units 20 nucleotides or more and that until now have not been systematically assessed genome-wide. We have surmounted critical sequencing barriers by establishing state-of-the-art long-read sequencing techniques to amplify and characterize the exact nucleotide sequence across tandem repeats. We recently reported the identification of a tandem repeat in WDR7 that is associated with Amyotrophic Lateral Sclerosis (ALS). Using the pipeline that we established for tandem repeat length estimation and validation, we propose to characterize human-specific tandem repeat expansions in AD. Our exciting preliminary analysis reveals many examples of repeats with increased or decreased length in AD. Several of these significantly differentially expanded repeats are in GWAS loci previously implicated in AD. Remarkably, the lead SNP at these loci is associated with stepwise changes in repeat length in individuals heterozygous or homozygous for the risk allele, suggesting that VNTRs may even play a causal role at these loci. We also identify rare instances of massive expansions, and/or internal sequence differences that depend on disease state. Our goal is to assess tandem repeats prone to expansion to estimate VNTR length genome- wide in AD to identify the contribution of novel repeat expansions in disease. We leverage large cohorts of whole genome sequence data from the Alzheimer’s Disease Sequencing Project. The thousands of genomes available means we can detect VNTR expansions in Hispanic, African American and Non- Hispanic White individuals as well as sex-specific effects of VNTR expansions. We will then perform targeted long-read sequencing of AD DNA samples to resolve the complete sequence of tandem repeats and define the consequence of internal sequence variation to AD. Finally, we will work to establish mechanisms of pathogenesis of novel tandem repeat expansions in AD. Our proposed studies will establish a novel paradigm to interrogate the mechanism of repeat expansion and will reveal insight into novel genetic factors that cause or modulate risk for AD.

阿尔茨海默氏病（AD）是最常见的神经退行性疾病之一，具有较高的全球性疾病 健康伯恩。尽管已经确定了几个AD遗传风险基因座，但这些基因组的因果变异 广泛的协会研究（GWAS）站点仍然是目的地密集的测序工作。重要的是， 但是，大多数全基因组测序方法无法准确解决串联重复，超过40个 这是神经系统疾病的关键驱动因素。我们假设很大一部分通用 对AD的贡献来自可变数字串联重复（VNTR），通常包含内部重复 单位20个或更多的核苷酸，到目前为止尚未系统地评估全基因组。我们 通过建立最先进的长阅读测序来克服关键测序障碍 扩增和表征整个串联重复序列的精确核苷酸序列的技术。我们最近 报道了WDR7中与肌萎缩性侧面相关的串联重复的鉴定 硬化症（ALS）。使用我们为串联重复长度估计和验证建立的管道， 我们建议表征AD中人类特异性的串联重复扩展。我们令人兴奋的初步 分析揭示了许多重复的例子，而AD的长度增加或减小。其中几个 先前与AD有关的GWAS基因座中的显着扩展重复序列。值得注意的是 这些局部的铅SNP与个体杂合的重复长度的逐步变化有关 或纯合的风险等位基因，表明VNTR甚至可能在这些基因座中起因果作用。我们 还确定依赖大规模扩张的罕见实例和/或内部序列差异 疾病状态。我们的目标是评估容易扩展的串联重复，以估计VNTR长度基因组 - 广泛的AD以确定疾病重复扩张的新作用。我们利用大量队列 来自阿尔茨海默氏病测序项目的整个基因组序列数据。成千上万 可用的基因组意味着我们可以在西班牙裔，非裔美国人和非 - 西班牙裔白人个人以及VNTR扩张的性别特定效果。然后我们将表演 AD DNA样品的有针对性的长阅读测序，以解决串联重复的完整顺序 并定义了内部序列变化对AD的结果。最后，我们将努力建立 AD中新型串联重复扩张的发病机理的机制。我们提出的研究将 建立一个新颖的范式来询问重复扩张的机制，并将揭示对 引起或调节AD风险的新型遗传因素。