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

剖析多效性背景下阿尔茨海默病易感性和血管特征的遗传和非遗传异质性

• 批准号: 10164704
• 负责人: ALEXANDER M KULMINSKI
• 金额: $ 56.45万
• 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: 2020-05-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10164704
• 关键词: Address; Admixture; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer’s disease biomarker; Applications Grants; Bioinformatics; Biological; Biology; Birth; Blood Glucose; Blood Vessels; Body mass index; Brain; Cardiovascular Diseases; Cell physiology; Cholesterol; Complement; Complex; Data; Development; Disease; Education; Ensure; Environmental Exposure; Epigenetic Process; Ethnic Origin; Etiology; Fibrinogen; Gene Expression; Genes; Genetic; Genetic Transcription; Genotype; Haplotypes; Heterogeneity; High Density Lipoproteins; Hypertension; Individual; Intervention; Link; Linkage Disequilibrium; Lipids; Low-Density Lipoproteins; Measures; Mediation; Methods; Methylation; Molecular Analysis; Molecular Profiling; Non-Insulin-Dependent Diabetes Mellitus; Onset of illness; Pathogenesis; Pathway interactions; Pattern; Persons; Physiology; Predisposition; Proxy; Publications; Quantitative Trait Loci; Race; Research; Risk; Risk Factors; Role; Signal Transduction; Smoking; Statistical Methods; Stroke; Structure; Tissues; Triglycerides; United States National Institutes of Health; Variant; Vascular Diseases; base; cognitive performance; cohort; dementia risk; density; exome; exome sequencing; genetic association; genetic linkage analysis; genetic variant; genome wide association study; indexing; insight; lifestyle factors; lipoprotein cholesterol; non-genetic; novel; personalized intervention; personalized therapeutic; phenotypic data; polygenic risk score; precision genetics; rare variant; resilience; sex; social; statistics; synergism; trait

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.):

NIH/NIA和阿尔茨海默氏症的关联强调，捕获阿尔茨海默氏病（AD）和与AD相关的痴呆症（AD/ADRD）的病因复杂性可能会大大提高对AD/ADRD发病机理的理解。复杂的机制可能涉及各种内源性（例如遗传学，表观遗传学，细胞，生理学）和外源性（例如，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，需要对复杂生物学的新颖见解和AD/ADRD的异质性，以开发有效的干预措施，这些干预措施可以针对一个人的独特风险特征量身定制。该项目的目的是确定个性化（即更均匀，特定组）的遗传和非遗传概况，其风险，保护和韧性在特定和多效性环境中对AD/ADRD和血管疾病的抗气和韧性。我们的方法利用了一系列综合方法，这些方法可确保在倾向于在多效性环境中倾向于AD/ADRD的遗传和非遗传异质性。这种方法克服了使用分析特定方法“一一”的不同因素的效果来表征不同因素的效果的严格研究的核心弱点。我们最近的出版物和现有研究的丰富数据支持我们方法的高潜力。我们将解决以下特定目的：目标1。从外部范围范围的关联研究中确定特定的和多效性位置的AD/ADRD和血管特征。 AIM 2。剖析异质性，利用分子特征分析被定义为受影响和未影响受试者的连锁dissequilbibrium模式的差异。目标3。使用严格的方法确定AD/ADRD特异性和多效风险，保护和弹性的个性化基因概况。 AIM 4。表征SNP的功能作用，来自这些SNP的基因的单个/极性变体和生物学作用。使用单个级基因表达和表观遗传学数据和摘要统计数据来表征SNP的转录途径，并从可用的表达和甲基化定量性状基因座研究中进行统计。）：：）：