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)的病因学复杂性可能大大促进对AD/ADRD发病机制的理解。复杂性的机制可能涉及各种内源性(如遗传学、表观遗传学、细胞学、生理学)和外源性(如环境暴露、社会环境)因素，包括血管起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有新的见解，以开发可根据个人独特的风险特征量身定做的有效干预措施。该项目的目标是在疾病特有和多效性的背景下，确定AD/ADRD和血管疾病的风险、预防和复原力的个性化(即，更同质的、特定于群体的)遗传和非遗传概况。我们的方法利用了一系列综合的方法，确保在多效性背景下解剖AD/ADRD易感性的遗传和非遗传异质性方面的协同作用。这种方法克服了以前使用分析特定方法“逐个”描述不同因素的影响的严谨性研究的核心弱点。我们方法的高潜力得到了我们最近的出版物和现有研究的丰富数据的支持。我们将致力于以下具体目标：目标1.从外显子组范围的关联研究中确定AD/ADRD和血管性状的特异性和多效性基因座。目的2.利用分子特征分析来剖析异质性，分子特征被定义为在受影响的受试者和未受影响的受试者中连锁不平衡模式的差异。目的3.使用严格的方法确定AD/ADRD特异性和多效性风险、保护和复原性的个性化基因图谱。目的4.从已确定的单基因/多基因变异中鉴定SNPs的功能作用以及这些SNPs的基因生物学作用。使用个人水平的基因表达和表观遗传学数据以及现有表达和甲基化数量性状基因座研究的汇总统计数据来表征SNPs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.):