Characterizing complex structural variation in Alzheimer's disease

项目总结 晚发性阿尔茨海默病(LOAD)是一种复杂的遗传疾病，被认为与 一些不同的基因座，包括结构变异(SVS)，这可以部分解释额外的缺失 遗传力和遗传背景。然而，SVS对负荷的影响还没有得到系统的研究， 而关于CNV与AD风险之间的关系的研究结果总体上是不一致的。为了弥补这一差距， 知识，我们建议通过利用先前的 产生了大规模的全基因组测序数据。为此，我们将系统地描述SVS 对39,000个来自多种族、表型良好的个体的样本进行了测序，作为阿尔茨海默氏症的一部分 疾病测序项目(ADSP)发现、扩展复制(ADSP-DEP)和后续数据集 (ADSP-FUS)，以及1000多个多用途家庭。识别与负荷相关的新的SVS可以 牵涉到以前未知的基因，并阐明可以用来产生 新的疗法和诊断标记物。

PROJECT SUMMARY Late-onset Alzheimer’s disease (LOAD) is genetically complex and thought to be associated with variants in a number of different loci, including structural variants (SVs), which could in part explain the additional missing heritability and genetic background. However, the impact of SVs on LOAD has not been systematically explored, while findings regarding CNV associations with AD risk have been overall inconsistent. To address this gap in knowledge, we propose to fully characterize the genetic architecture of SVs in LOAD by leveraging previously generated large-scale whole genome sequencing data. To this end, we will systematically characterize SVs across 39,000 samples from multi-ethnic, well-phenotyped individuals sequenced as a part of Alzheimer’s Disease Sequencing Project (ADSP) discovery, extension replication (ADSP-DEP) and follow-up datasets (ADSP-FUS), as well as in over 1000 multiplex families. Identification of novel SVs associated with LOAD could implicate previously unknown genes and elucidate biological mechanisms that could be leveraged to generate novel therapeutics and diagnostic markers.