Personalized genetic profiles of risk and resilience in Alzheimer's and vascular diseases

先前的研究和2018年NIA-Alzheimer's-Association框架强调， 阿尔茨海默病（AD）的复杂生物学和异质性需要开发有效的 可以针对个人独特的风险状况采取干预措施。这些特征很可能是 AD许多遗传和非遗传风险和保护因素相互作用，包括血管 起源，很难解开。新出现的证据也表明，AD和血管 疾病往往聚集在一起。本项目涉及PAR-17-054关于解开 遗传和AD/血管风险因素在AD风险和恢复力中的异质性相互作用，包括 通过利用现有资源和开展活动， 统计力量我们的方法结合了全基因组关联研究的彻底方法， 在大样本的候选人样方法的严谨性，是建立在：（一）进化的核心原则， AD遗传学中的生物学和生殖后生活的其他年龄相关特征， 与遗传易感性的固有异质性，这些性状，（ii）从以前的研究， 这些特征（包括我们自己的工作），以及（iii）我们大规模研究的有希望的结果，证明其 重要性、可行性和利用现有资源大幅提高电力的潜力。这 研究有助于更好地了解以往研究在严谨性方面的弱点， 令人信服的证据表明，我们的方法是一种自然和关键的战略，以推动在以下方面取得进展： 剖析AD和血管特征的内在异质性机制。目标是确定 个性化（即，风险和复原力的单基因/多基因特征 在疾病特异性和多效性背景下， 来自本项目计划的以AD为中心的多效性荟萃分析的信息和既往 我们和其他研究小组的分析，并确定AD风险和其他因素在这些 数据区.我们将致力于实现以下具体目标：目标1。确定AD的特异性和多效性基因座 和血管特征的新的分析和现有的研究。目标二。剖析异质性利用 分子标记的分析定义为连锁不平衡结构的差异， 受影响和未受影响的受试者。目标3。确定AD特异性和 多效性风险和复原力。目标4。从确定的SNP中表征SNP的功能作用， 单基因/多基因变体和这些SNP的基因的生物学作用。表征转录 使用个体水平的基因表达和表观遗传学数据和汇总统计的SNP途径 从现有的表达和甲基化数量性状基因座研究。

Prior research and the 2018 NIA-Alzheimer’s-Association framework emphasize that novel insights into the complex biology and heterogeneity of Alzheimer’s disease (AD) are needed to develop efficient interventions that can be tailored to persons’ unique risk profiles. These profiles are likely a result of an interplay of many genetic and non-genetic risk and protective factors for AD, including those of vascular origin, which are difficult to disentangle. Emerging evidence suggests also that ADs and vascular diseases tend to cluster together. This project addresses an objective of PAR-17-054 on disentangling heterogeneous interactions of genetic and AD/vascular risk factors in risk and resilience to AD, including age-specific effects, by leveraging existing resources and engaging in activities that will improve statistical power. Our approach, combining thorough methods of genome-wide association studies and the rigor of the candidate-like methods in large samples, is built on: (i) core principles of evolutionary biology in genetics of AD and other age-related traits characteristic of post-reproductive life, which deals with an inherent heterogeneity in genetic predisposition to such traits, (ii) insights from prior studies of such traits (including our own work), and (iii) promising results of our large-scale studies proving its significance, feasibility, and potential to substantially improve power using the existing resources. This research contributed to better understanding of weaknesses in the rigor of prior studies and provided compelling evidence that our approach is a natural and critical strategy to advance the progress in dissecting the inherently heterogeneous mechanisms of AD and vascular traits. The goal is to identify personalized (i.e., more homogeneous, group-specific) mono/polygenic profiles of risks and resilience to AD and vascular diseases in the disease-specific and pleiotropic contexts in prioritized loci leveraging information from the AD-centered pleiotropic meta-analysis planned in this project and previous analyses by our and other research groups, and identify the role of AD risk and other factors in these profiles. We will address the following specific aims: Aim 1. Identify specific and pleiotropic loci for AD and vascular traits from new analyses and the existing studies. Aim 2. Dissect heterogeneity leveraging the analysis of molecular signatures defined as differences in linkage disequilibrium structures in affected and unaffected subjects. Aim 3. Identify personalized genetic profiles of AD-specific and pleiotropic risks and resilience. 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.