Statistical and computational methods for integrative analysis of Alzheimer's Disease genetics

阿尔茨海默病遗传学综合分析的统计和计算方法

• 批准号: 10411994
• 负责人: Zihuai He
• 金额: $ 70.6万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10411994
• 关键词: African American; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Base Pairing; Biological Markers; Brain; Caribbean Hispanic; Case-Control Studies; Caucasians; Cerebrospinal Fluid; Code; Collaborations; Computing Methodologies; Data; Development; Elements; Encyclopedia of DNA Elements; Epigenetic Process; Ethnic group; Family; Family Study; Fostering; Future; Gene Expression Regulation; Genes; Genetic; Genetic Diseases; Genetic Variation; Genome; Genomics; Goals; Health; Heritability; Hispanic Americans; Human; Human Genome; Image; Large-Scale Sequencing; Longitudinal Studies; Medicine; Memory; Meta-Analysis; Methodology; Methods; Mission; Observational Study; Outcome; Pathogenesis; Phenotype; Play; Proteins; Public Health; Research; Risk; Role; Sampling; Scanning; Signal Transduction; Statistical Methods; Technology; Testing; Time; Tissues; United States National Institutes of Health; Untranslated RNA; Variant; Work; cell type; cohort; data integration; design; epigenomics; exome; flexibility; functional genomics; gene therapy; genetic analysis; genetic architecture; genetic testing; genome annotation; genome sequencing; genome wide association study; genome-wide; genomic data; imaging biomarker; improved; innovation; insight; neuroimaging; novel; personalized medicine; phenotypic data; rare variant; religious order study; risk variant; sex; targeted exome sequencing; web site; whole genome

Project Summary/Abstract Genetic factors play an important role in the development of Alzheimer's disease. While much progress has been made in Alzheimer’s disease genetics, the role of noncoding variants is largely unknown. The noncoding genome covers ~98% of the human genome and includes elements that regulate when, where, and to what degree protein-coding genes (e.g. APOE) are transcribed. The objective of this proposal will be to focus specifically on the analysis of whole-genome sequencing studies of Alzheimer’s disease, in order to identify rare noncoding variants and characterize their role in Alzheimer’s disease pathogenesis. We will attain our objective via an innovative approach, combining whole-genome sequencing, epigenetic technologies and multi-layered phenotypic data such as imaging and biomarkers. This will lead to a unique combination of methodologies for the analysis of noncoding variants, allowing for absence of natural units (e.g. genes) for testing (Aim 1), integration of multi-layer information for enhancing power (Aim 2), and biologically meaningful interpretation of association signals (Aim 3). The proposed methods will be applied to a total of roughly 20,000 whole genomes unifying the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Alzheimer's Disease Sequencing Project (ADSP), the Religious Orders Study and Memory and Aging Project (ROSMAP) and a newly established cohort, the Stanford Extreme Phenotypes in Alzheimer's Disease (StEP AD). We expect that the application of the proposed methods will significantly improve our understanding of the genetic architecture of Alzheimer's disease and, critically, provide a set of well-defined, novel targets for the development of genomic-driven medicine.

项目摘要/摘要 遗传因素在阿尔茨海默氏病的发展中起着重要作用。虽然进步很大 他是在阿尔茨海默氏病遗传学中造成的，非编码变体的作用在很大程度上是未知的。非编码 基因组覆盖了约98％的人类基因组，其中包括调节何时，何地和到什么的元素 度蛋白质编码基因（例如APOE）被转录。该提议的目的是集中精力 特别是针对阿尔茨海默氏病全基因组测序研究的分析，以确定 罕见的非编码变体并表征了它们在阿尔茨海默氏病发病机理中的作用。我们将达到我们的 通过创新方法的目标，结合全基因组测序，表观遗传技术和 多层表型数据，例如成像和生物标志物。这将导致独特的组合 分析非编码变体的方法，允许缺乏天然单元（例如基因） 测试（AIM 1），多层信息的集成以增强功率（AIM 2）以及生物学上 对关联信号的有意义解释（目标3）。提出的方法将用于总计 大约有20,000个全基因组统一了阿尔茨海默氏病神经影像学计划（ADNI）， 阿尔茨海默氏病测序项目（ADSP），宗教秩序研究与记忆和衰老项目 （Rosmap）和新成立的队列，是阿尔茨海默氏病的斯坦福极端表型（步骤） 广告）。我们希望提出的方法的应用将显着提高我们对 阿尔茨海默氏病的遗传结构，并至关重要，为一组定义明确的新型目标提供了 基因组驱动医学的发展。