A comprehensive study of tandem repeat variation as a cause of Alzheimer's disease

串联重复变异作为阿尔茨海默病病因的综合研究

• 批准号: 10585034
• 负责人: Andrew James Sharp
• 金额: $ 220.63万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585034
• 关键词: Algorithms; Alleles; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease risk; Base Pairing; Bioinformatics; Biological Markers; Case/Control Studies; Clinical; Communities; Copy Number Polymorphism; Custom; DNA; Data; Dementia; Diagnosis; Dideoxy Chain Termination DNA Sequencing; Diploidy; Disease; Drosophila genus; Exhibits; Frequencies; Frontotemporal Dementia; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genome; Genotype; Human; Human Genome; Huntington Disease; Individual; Inherited Spinocerebellar Degenerations; Knowledge; Late Onset Alzheimer Disease; Length; Link; Meiosis; Minisatellite Repeats; Modeling; Mutation; Nature; Nerve Degeneration; Neurodegenerative Disorders; Normal Range; Pathogenicity; Patients; Phenotype; Publishing; Resource Sharing; Resources; Risk; Role; Sampling; Short Tandem Repeat; Stretching; Tandem Repeat Sequences; Toxic effect; Trans-Omics for Precision Medicine; Trinucleotide Repeats; Variant; bioinformatics tool; causal variant; cell repository; cohort; comparison control; endophenotype; exome sequencing; familial Alzheimer disease; genetic pedigree; genetic risk factor; genome browser; genome sequencing; genome-wide; high standard; large datasets; nervous system disorder; neuroimaging; novel; segregation; whole genome

Tandem Repeat Expansions (TREs), most commonly of triplet repeats such as poly(CAG), are known to underlie >40 different human neurological diseases. While the majority of TREs identified to date have been found in late-onset neuro-degenerative disorders such as hereditary ataxias and Huntington disease, TREs have been identified in patients with AD and certain types of dementia. In addition to these expansions of short tandem repeats (STRs, with motif sizes between 1 and 6 base pairs), copy number variation of larger repeats with motifs ≥10bp, also known as Variable Number of Tandem Repeats (VNTRs), has recently been linked to risk of AD. However, despite this evidence that variation in tandem repeat (TR) sequences can act as the causative mutations in some cases of AD and dementia, there have been no concerted efforts in AD cohorts to either systematically screen for novel TREs, or to genotype VNTR copy numbers. Newly developed bioinformatic approaches that can be applied to analyze Whole Genome Sequencing (WGS) data now provide an opportunity to fill this knowledge gap. Utilizing the expertise and knowledge that we have gained working on other large datasets, we propose to apply these approaches to analyze ~62,000 genomes sequenced by the Alzheimer's Disease Sequencing Project that are available to the community, in addition to a further ~48,000 control genomes from TOPMed, and will use these data to investigate two major hypotheses: 1. We hypothesize that some cases of AD are caused by rare, highly penetrant pathogenic TREs. Using novel bioinformatic tools that can identify TREs, we will search for rare TREs that are observed only in AD samples, or which show significant enrichment in AD cases compared to controls, and thus are likely causative for AD. Potentially pathogenic TREs will then be validated by PCR or long-read sequencing in available DNA samples. 2. We hypothesize that common polymorphic copy number variation of TRs of all motif sizes can act as genetic risk factors for AD. Short tandem repeats (STRs) with motif sizes 1-6bp will be genotyped with hipSTR. VNTRs will be genotyped using read depth to estimate diploid copy number. We will analyze available WGS data from ~20,000 sporadic late-onset AD samples and ~90,000 unrelated controls, generating copy number estimates for >1 million STRs and ~150,000 VNTRs genome-wide, which will be used to perform association analysis of TR copy number with AD status in a case:control study. Given that TREs, and polymorphic variation in STRs and VNTRs, both represent established mutational mechanisms that contribute to a variety of late-onset neuro-degenerative conditions, we believe that the study of TRs in AD represents a logical step that has a high likelihood of uncovering novel genetic causes of AD.

串联重复膨胀（TRE），最常见的是诸如poly（cag）之类的三胞胎重复序列，已知 基础> 40种不同的人类神经疾病。迄今已确定的大多数TRE 在晚期神经化学疾病中发现，例如遗传性行为和亨廷顿疾病，TRE 已经在AD和某些类型的痴呆症患者中鉴定出来。除了这些简短的扩展 串联重复（Strs，主题大小在1到6个碱基对之间），较大重复的拷贝数变化 据主题≥10bp，也称为可变数量的串联重复序（VNTR），最近已与 AD风险。但是，要求这一证据表明串联重复（TR）序列的变化可以充当 在某些AD和痴呆症的情况下，因果突变，在AD队列中没有一致的努力 要么系统地筛选新的TRE，要么对基因型VNTR副本编号进行筛选。 新开发的生物信息学方法可用于分析整个基因组测序 （WGS）数据现在提供了填补这一知识差距的机会。利用专业知识和知识 我们已经在其他大型数据集上工作了，我们建议采用这些方法来分析约62,000 由阿尔茨海默氏病测序项目测序的基因组，可供社区， 除了TopMed的另外约48,000个对照基因组，并将使用这些数据研究两个主要 假设： 1。我们假设某些AD病例是由罕见，高度渗透的致病性TRE引起的。使用 可以识别TRE的新型生物信息学工具，我们将搜索仅在AD中观察到的稀有TRE 与对照组相比，样本或在AD病例中显示出明显富集的样品，因此 AD的病因。然后，可能会通过PCR或长阅读测序来验证潜在的致病性TRE 可用的DNA样品。 2.我们假设所有图案大小的TRS的常见多态性拷贝数变化可以充当 AD的遗传危险因素。短的串联重复序列（STR）具有1-6bp的基序尺寸的基因分型 HIPSTR。 VNTR将使用读取深度进行基因分型，以估计二倍体拷贝数。我们将分析 可用的WGS数据来自约20,000个零星发作的广告样本和约90,000个无关的对照， 生成> 100万str和〜150,000 VNTR基因组的拷贝数估计值，这将是 用于在案例中对TR拷贝数进行与AD状态的关联分析：控制研究。 鉴于TRE和Strs和VNTR中的多态性变化，都代表已建立的突变 有助于各种迟到神经化学条件的机制，我们认为该研究 AD中的TRS代表了一个逻辑步骤，其很有可能会发现AD的新遗传原因。