Alzheimer variants: Propagation of shared functional changes across cellular networks

项目摘要 阿尔茨海默病(AD)和相关疾病(ADRD)的遗传学研究已经确定了72个以上的相关基因座 有敏感度。尽管一些最具渗透性的变体已经被独立研究，但大多数 序列变体和特征的组合不太可能孤立地起作用。此外，易感基因座的范围覆盖 基因组的编码、表观遗传和调节区，暗示着复杂的关系 仅通过大规模转录和蛋白质组学分析就能捕捉到。考虑到这一点，我们系统地 以细胞自主和非自主方式询问经过验证的AD基因座上的变异组合 使用分子、表观遗传学和功能分析相结合的方法。这样就可以创建功能正常的网络 跨AD基因座，并识别单个基因座的影响相互作用的节点处，以触发 AD病理和临床表型。作为这项工作的一部分，我们建议建立一个新的AD轨迹注释器 从参考数据库中合成与AD相关的序列特征信息的接口 包括现有的多组学和临床数据，以及捕获定量蛋白质形式的新数据集 和细胞功能数据；后两种数据形式在AD研究中被低估了 但对识别跨基因座交互作用至关重要。从这一综合数据分析和门户努力中， 然后，我们建立了一套基因编辑工作，以验证和扩展我们对多基因编辑的机械理解 来自这些AD相关序列特征的基因座功能网络。总而言之，这些分析和 实验使我们能够将AD相关基因变异的异质性和临床表现联系起来 一个连贯的框架，将AD基因座与AD发病和进展中的事件的时间序列联系起来。

Project Abstract Genetic studies of Alzheimer’s disease (AD) and related-diseases (ADRD) have identified over 72 loci associated with susceptibility. Although some of the most penetrant variants have been studied independently, the majority of sequence variants and features are unlikely to act in isolation. In addition, the range of susceptibility loci cover coding, epigenetic, and regulatory regions of the genome, suggesting complex relationships that cannot be captured by large-scale transcriptomic and proteomic profiling alone. With this in mind, we systematically interrogate combinations of variants across validated AD loci in a cell autonomous and non-autonomous manner using a combination of molecular, epigenetic, and functional assays. This allows to create a functional network across AD loci, and identify nodal points where the effects of individual loci interact to trigger the hallmarks of AD pathology and clinical phenotypes. As part of this effort, we propose to establish a novel AD Locus Annotator interface that synthesizes information about AD-associated sequence features from reference databases encompassing existing multi-omic and clinical data, as well as new data sets that capture quantitative proteoform and cellular functional data; these latter two data modalities have been under-characterized in AD research to date, but are crucial to identifying cross-loci interactions. From this synthesized data analysis and portal effort, we then establish a set of gene editing efforts to validate and extend our mechanistic understanding of multi- locus functional networks from these AD-associated sequence features. Taken together, these analyses and experiments allow us to link the heterogeneity of AD-associated genetic variation and clinical manifestations into a coherent framework that link AD loci with the temporal sequence of events in AD onset and progression.