Characterizing complex structural variation in Alzheimer's disease

项目摘要 晚发性阿尔茨海默病（LOAD）是一种遗传复杂的疾病， 许多不同的基因座，包括结构变异（SV），这可以部分解释额外的缺失 遗传力和遗传背景。然而，SV对LOAD的影响尚未得到系统的研究， 而关于CNV与AD风险相关性的研究结果总体上不一致。为了弥补这一差距， 知识，我们建议充分表征遗传结构的SV在负载利用以前 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SV 在39,000个来自多种族，表型良好的个体的样本中，作为阿尔茨海默氏症的一部分进行测序， 疾病测序项目（ADSP）发现、延伸复制（ADSP-DEP）和随访数据集 （ADSP-FUS），以及超过1000个多路复用家庭。识别与LOAD相关的新SV可以 涉及以前未知的基因和阐明生物机制，可以利用产生 新的治疗剂和诊断标记物。

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.