Dissecting genetic and non-genetic heterogeneity in predisposition to Alzheimer's disease and vascular traits in pleiotropic context

NIH/NIA和阿尔茨海默病协会强调，捕捉阿尔茨海默病（AD）和AD相关痴呆（AD/ADRD）病因的复杂性可能会大大推进对AD/ADRD发病机制的理解。复杂性的机制可能涉及各种内源性（例如，遗传学、表观遗传学、细胞学、生理学）和外源性（例如，环境暴露、社会环境）因素，包括血管来源的因素及其相互作用。人们认识到，需要对AD/ADRD的复杂生物学和异质性的新见解，以开发可针对个人独特风险特征的有效干预措施。该项目的目标是确定个性化（即，在疾病特异性和多效性背景下，AD/ADRD和血管疾病的风险、预防和恢复力的遗传和非遗传概况。我们的方法利用了一系列综合方法，确保在多效性背景下解剖AD/ADRD易感性中的遗传和非遗传异质性的协同作用。这种方法克服了先前研究的核心弱点，即使用特定分析方法“逐个”表征不同因素的影响。我们最近的出版物和现有研究的丰富数据支持了我们方法的高潜力。我们将致力于实现以下具体目标：目标1。从全外显子组关联研究中确定AD/ADRD和血管性状的特异性和多效性位点。目标2.利用分子特征分析剖析异质性，分子特征定义为受影响和未受影响受试者中连锁不平衡模式的差异。目标3.使用严格的方法确定AD/ADRD特异性和多效性风险，保护和恢复力的个性化遗传特征。目标4。从已鉴定的单基因/多基因变体中表征SNP的功能作用以及这些SNP的基因的生物学作用。使用个体水平的基因表达和表观遗传数据以及来自可用表达和甲基化数量性状基因座研究的汇总统计来表征SNP的转录途径。

NIH/NIA and Alzheimer’s association emphasize that capturing complexity in etiology of Alzheimer’s disease (AD) and AD-related dementias (AD/ADRD) may substantially advance the understanding of the AD/ADRD pathogenesis. Mechanisms of complexity may involve various endogenous (e.g., genetics, epigenetic, cellular, physiology) and exogenous (e.g., environmental exposures, social milieu) factors, including those of vascular origin, and their interactions. It is recognized that novel insights into the complex biology and heterogeneity of AD/ADRD are needed to develop efficient interventions that can be tailored to a person’s unique risk profile. The objective of this project is to identify personalized (i.e., more homogeneous, group-specific) genetic and non-genetic profiles of risk of, protection against, and resilience to AD/ADRD and vascular diseases in the disease-specific and pleiotropic contexts. Our approach leverages an array of comprehensive methods which ensure synergism in dissecting genetic and non-genetic heterogeneity in predisposition to AD/ADRD in pleiotropic context. This approach overcomes core weakness in the rigor of prior studies characterizing effects of different factors “one by one” using analysis-specific methods. High potential of our approach is supported by our recent publications and rich data from the existing studies. We will address the following specific aims: Aim 1. Identify specific and pleiotropic loci for AD/ADRD and vascular traits from the exome-wide association study. Aim 2. Dissect heterogeneity leveraging the analysis of molecular signatures defined as differences in linkage disequilibrium patterns in affected and unaffected subjects. Aim 3. Identify personalized genetic profiles of AD/ADRD-specific and pleiotropic risks, protection, and resilience using rigorous methods. Aim 4. Characterize the functional roles of SNPs from the identified mono/polygenic variants and biological roles of genes for these SNPs. Characterize transcription pathways for SNPs using individual-level gene expression and epigenetic data and summary statistics from the available expression and methylation quantitative trait loci studies.):