Investigating tandem repeat variation as a cause of Alzheimer's disease from exome sequencing data

根据外显子组测序数据研究串联重复变异是阿尔茨海默氏病的原因

基本信息

批准号：
10337187
负责人：
Andrew James Sharp
金额：
$ 16.9万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-15 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10337187
关键词：
Algorithms Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Alzheimer&apos s disease risk Base Pairing Bioinformatics Case-Control Studies Communities Copy Number Polymorphism DNA Data Data Set Dementia Diagnosis Dideoxy Chain Termination DNA Sequencing Frontotemporal Dementia Funding Genes Genetic Genotype Grant Human Huntington Disease Inherited Spinocerebellar Degenerations Knowledge Late Onset Alzheimer Disease Lead Length Link Methods Minisatellite Repeats Mutation Nature Nerve Degeneration Neurodegenerative Disorders Pathogenicity Patients Phenotype Predisposition Research Research Personnel Sampling Short Tandem Repeat Stretching Tandem Repeat Sequences Trinucleotide Repeats United States National Institutes of Health Variant base bioinformatics tool case control causal variant cell repository cohort exome exome sequencing genetic risk factor genome sequencing genome wide association study large datasets member nervous system disorder novel novel strategies whole genome

项目摘要

Tandem Repeat Expansions (TREs), most commonly of triplet repeats such as poly(CAG), are known to underlie >30 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 expansions of short tandem repeats (those with motif sizes between 1 and 6 base pairs), copy number variation of larger repeats with motifs ≥20bp, 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 Exome Sequencing (WES) 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 >20,0000 exomes generated by the Alzheimer's Disease Sequencing Project that are available to the community, and will use these data to investigate two 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 VNTRs can act as genetic risk factors for AD. We have developed a novel approach based on read depth to estimate copy number of VNTRs from exome sequencing data. We will analyze available WES data from 9,226 sporadic AD samples and 10,151 unrelated controls, generating copy number estimates for ~4,100 genic VNTRs that are represented in WES, which will be used to perform association analysis of VNTR copy number with AD status in a case:control study. Given that TREs, and polymorphic variation in VNTRs, both represent established mutational mechanisms that contribute to a variety of late-onset neuro-degenerative conditions, we believe that the study of TR variation 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> 30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。除了简短的扩展串联重复序（具有1到6个碱基对之间的图案大小的重复序列），较大重复序列的拷贝数变化对于≥20bp的基序，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外显子组测序（WES）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> 20,0000 由阿尔茨海默氏病测序项目产生的外体可供社区，以及将使用这些数据调查两个假设： 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VNTR的常见多态性拷贝数变化可以充当遗传风险 AD的因素。我们已经根据阅读深度开发了一种新颖的方法，以估计拷贝数来自外显子测序数据的VNTR。我们将分析来自9,226个零星广告的可用WES数据样品和10,151个无关的控件，生成〜4,100个基因VNTR的拷贝数估计值在WES中表示，将用于执行VNTR副本编号的关联分析案例中的广告状态：控制研究。鉴于TRE和VNTR中的多态性变化都代表了已建立的突变机制，有助于各种晚期神经脱生条件，我们认为TR差异的研究 AD代表了一个逻辑步骤，其很有可能会发现AD的新遗传原因。