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

串联重复序列扩展(TRE)，最常见的三联体重复序列，如聚(CAG)，已知 40种不同的人类神经疾病的基础。虽然到目前为止确定的大多数TRE是 发现于迟发性神经退行性疾病，如遗传性共济失调和亨廷顿病 已经在阿尔茨海默病和某些类型的痴呆症患者中被发现。除了这些空头的扩展 串联重复(STR，基序大小在1到6个碱基对之间)，较大重复的拷贝数变化 通过基序≥10bp，也被称为可变数量的串联重复序列(VNTRs)，最近被连接到 AD的风险。然而，尽管有证据表明串联重复序列(TR)的变异可以作为 在一些阿尔茨海默病和痴呆症病例中的致病突变，AD队列中没有一致的努力来 要么系统地筛选新的tre，要么对vntr拷贝数进行分型。 可用于全基因组测序分析的生物信息学新方法 (WGS)数据现在提供了填补这一知识缺口的机会。利用专业技术和知识 我们已经在其他大型数据集上获得了工作成果，我们建议应用这些方法来分析~62,000 由阿尔茨海默病测序项目测序的基因组，可供社区使用，在 除了来自TOPMed的另外约48,000个对照基因组外，还将利用这些数据研究两个主要的 假设： 1.我们假设某些AD病例是由罕见的高渗透性致病树引起的。vbl.使用 新的生物信息学工具可以识别TRE，我们将搜索仅在AD中观察到的稀有TRE 样本，或者与对照组相比在AD病例中显示显著丰富的样本，因此很可能 导致阿尔茨海默病。然后，将通过聚合酶链式反应或长读测序来验证潜在的致病TRES 可获得的DNA样本。 2.我们假设所有基序大小的TRs的共同多态拷贝数变异可以作为 阿尔茨海默病的遗传危险因素。基序大小为1-6bp的短串联重复序列(STR)将进行基因分型 HIPSTR。将使用读取深度对VNTRs进行基因分型，以估计二倍体拷贝数。我们将分析 来自大约20,000个零星的晚发性AD样本和大约90,000个无关对照的WGS数据， 为全基因组范围内的100万个STR和~150,000个VNR生成拷贝数估计，这将是 用于在病例对照研究中进行TR拷贝数与AD状态的关联分析。 鉴于TRES以及STR和VNTRs的多态变异，两者都代表已建立的突变 导致各种迟发性神经退行性疾病的机制，我们认为这项研究 阿尔茨海默病中TRs的发现代表着一个合乎逻辑的步骤，它很有可能发现AD的新遗传原因。

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.