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

先前的研究和2018年NIA-阿尔茨海默氏症协会框架强调，对 阿尔茨海默病(AD)需要复杂的生物学和异质性才能开发出有效的 可以根据个人独特的风险特征量身定做的干预措施。这些配置文件很可能是 阿尔茨海默病的许多遗传和非遗传风险和保护因素的相互作用，包括血管风险因素 起源，这是很难解开的。新出现的证据还表明，ADS和血管 疾病往往聚集在一起。该项目解决了PAR-17-054关于解开纠缠的目标 遗传和阿尔茨海默病/血管危险因素在阿尔茨海默病风险和复原力中的异质性交互作用，包括 年龄效应，通过利用现有资源和参与将会改善的活动 统计学上的力量。我们的方法，结合了全基因组关联研究的彻底方法和 在大样本中类似候选方法的严谨性建立在：(I)进化的核心原则 阿尔茨海默病遗传学中的生物学和其他生殖后生活的年龄相关特征，这涉及到 这些性状的遗传易感性具有内在的异质性，(Ii)从先前的研究中获得的见解 这些特征(包括我们自己的工作)，以及(Iii)我们的大规模研究证明其 利用现有资源大幅提高电力的重要性、可行性和潜力。这 研究有助于更好地了解先前研究的严谨性中的弱点，并提供 令人信服的证据表明，我们的方法是推动在以下方面取得进展的自然和关键战略 剖析AD与血管性状的内在异质性机制。我们的目标是确定 风险和复原力的个人化(即更加同质、特定于群体)单基因/多基因概况 AD和血管疾病在疾病特异性和多效性背景下的优先基因座杠杆作用 来自本项目和以前计划的以AD为中心的多效性荟萃分析的信息 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方面的作用 配置文件。我们将解决以下具体目标：目标1.确定AD的特定和多效性基因座 以及来自新的分析和现有研究的血管特征。目标2.剖析异构性 分子特征的分析定义为连接不平衡结构的差异。 受影响和未受影响的受试者。目的3.确定阿尔茨海默病患者的个性化基因图谱 多效性风险和韧性。目的4.从已识别的SNPs中表征SNPs的功能作用 这些SNPs的单/多基因变异和基因的生物学作用。描述转录的特征 利用个体水平的基因表达、表观遗传学数据和汇总统计研究SNPs的途径 从可获得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.