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

阿尔茨海默病和血管疾病的风险和恢复力的个性化基因图谱

• 批准号: 10338056
• 负责人: ALEXANDER M KULMINSKI
• 金额: $ 76.06万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10338056
• 关键词: Address; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Bioinformatics; Biological; Biology; Birth; Blood Glucose; Blood Pressure; Blood Vessels; Body mass index; Cardiovascular Diseases; Characteristics; Cholesterol; Complex; Data; Development; Diastolic blood pressure; Disease; Education; Environmental Exposure; Epigenetic Process; Ethnic Origin; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Genetic Transcription; Genotype; Goals; Haplotypes; Heterogeneity; High Density Lipoproteins; Hypertension; Individual; Intervention; Life; Link; Linkage Disequilibrium; Lipids; Low-Density Lipoproteins; Mediation; Meta-Analysis; Methods; Methylation; Molecular Analysis; Molecular Profiling; Non-Insulin-Dependent Diabetes Mellitus; Onset of illness; Pathway interactions; Pattern; Persons; Physical activity; Proxy; Quantitative Trait Loci; Race; Research; Resources; Risk; Risk Factors; Role; Sampling; Smoking; Statistical Methods; Stroke; Structure; Triglycerides; Variant; Vascular Diseases; Work; age related; base; cognitive performance; cohort; density; disease phenotype; exome; genetic association; genetic variant; genome wide association study; genome-wide analysis; improved; indexing; insight; lifestyle factors; lipoprotein cholesterol; non-genetic; novel; personalized intervention; personalized therapeutic; polygenic risk score; precision genetics; protective factors; rare variant; reproductive; resilience; sex; statistics; trait; vascular risk factor

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.

先前的研究和2018年Nia-Alzheimer的协会框架强调了新颖的见解 需要提高阿尔茨海默氏病（AD）的复杂生物学和异质性来发展有效 可以针对人们独特的风险概况量身定制的干预措施。这些配置文件可能是 许多遗传和非遗传风险和AD保护因素的相互作用，包括血管 起源很难解开。新兴证据也表明广告和血管 疾病倾向于聚集在一起。该项目解决了第17-054届PAR的目标 遗传和AD/血管危险因素的异质相互作用在风险和对AD的韧性中的异质相互作用，包括 特定年龄的影响，利用现有资源并从事可以改善的活动 统计能力。我们的方法结合了全基因组关联研究的彻底方法和 大型样本中类似候选方法的严格性是建立在以下基础上的：（i）进化的核心原理 在AD遗传学和其他与年龄有关的特征的生物学中，后代生命的特征 在遗传性易感性中继承了这种特征的异质性，（ii）先前研究的见解 这些特征（包括我们自己的工作）和（iii）我们大规模研究的有希望的结果证明了它的 使用现有资源的意义，可行性和潜力，可以实质上提高功率。这 研究有助于更好地了解先前研究的严格性弱点，并提供 令人信服的证据表明，我们的方法是一种自然而关键的策略，以促进进步 解剖AD和血管性状的固有异质机制。目标是确定 个性化（即更均匀，特定组的）单或多基因概况的风险和弹性概况 在优先级的疾病特异性和多效环境中，在疾病特异性和多效性环境中进行AD和血管疾病的优先级。 来自该项目和以前的计划中计划的以广告为中心的多效性荟萃分析的信息 通过我们和其他研究小组进行分析，并确定AD风险和其他因素的作用 概况。我们将解决以下特定目的：目标1。确定AD的特定和多效基因座 以及新分析和现有研究的血管特征。目标2。剖析异质性利用 分子特征的分析被定义为链接二动结构的差异 目标3。确定广告特异性的个性化基因概况 多效风险和弹性。 AIM 4。表征SNP的功能作用 这些SNP的基因的单/聚合物变体和生物学作用。特征转录 使用个体级基因表达和表观遗传数据和摘要统计的SNP途径 根据可用的表达和甲基化定量性状基因座研究。