Epidemiological Integration of Genetic Variants and Metabolomics Profiles in Washington Heights Columbia Aging Project

华盛顿高地哥伦比亚老龄化项目中遗传变异和代谢组学概况的流行病学整合

• 批准号: 10055447
• 负责人: RICHARD P MAYEUX
• 金额: $ 871.04万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10055447
• 关键词: African American; Age; Aging; Alcohols; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease risk; Biochemical; Biological; Biological Assay; Blood; Caribbean Hispanic; Chemicals; Clinical Data; Cognitive; Cohort Studies; Collection; Communities; DNA; Data; Data Set; Dementia; Development; Dietary Practices; Disease; Disease Progression; Elderly; Environmental Risk Factor; Epidemiology; Equation; Ethnic group; Framingham Heart Study; Genes; Genetic; Genetic Risk; Genome; Glycosphingolipids; Goals; Human; Human body; Impaired cognition; Individual; Investigation; Life Style; Link; Measures; Mediating; Mediation; Medical; Memory; Meta-Analysis; Metabolism; Neurologic; Neurologic Examination; Not Hispanic or Latino; Participant; Pathway interactions; Phenotype; Physical activity; Physiological; Plasma; Registries; Resources; Risk; Risk Factors; Severities; Severity of illness; Sleep; Smoking; Sphingomyelins; Telephone Interviews; Testing; Time; Washington; Wisconsin; base; biomarker development; cerebrovascular; cognitive testing; cohort; exome sequencing; follow-up; functional genomics; gene environment interaction; genetic analysis; genetic risk factor; genetic variant; genome sequencing; genome wide association study; in vivo; informant; lifestyle factors; longitudinal analysis; longitudinal design; medical examination; metabolome; metabolomics; molecular phenotype; neuroimaging; polygenic risk score; protective factors; racial and ethnic; religious order study; response; sex; standard measure; therapeutic development

ABSTRACT Metabolites reflect the dynamic, qualitative and quantitative changes in humans and provide a functional assessment of the physiological state of individuals with and without disease. The metabolome represents the closest link between the phenotype and the underlying biochemical layers of the genome. In the human body, metabolites are chemically transformed during metabolism in response to genetic and environmental factors in the causal pathway to a disease or to an in vivo change as a result of the disease. The human metabolome has been studied in Alzheimer's disease (AD) in a small number of cross-sectional and longitudinal investigations with limited numbers of ethnic groups and little or no concurrent genetic analyses. The Washington Heights, Inwood Columbia Aging Project is a multi-ethnic cohort that has collected clinical data and biological resources for several years with the goal of identifying the environmental and genetic risk factors and causes of AD. The cohort is ideally suited for this project because 23% are non-Hispanic whites, 29% are African Americans and 48% are Caribbean Hispanics, and because loss-to-follow up has been minimal due to the use of a validated telephone interview of the participants and informants. We have conducted medical and neurological examinations, cognitive assessments and captured environmental/lifestyle risk and protective factors in this longitudinal investigation at 18-month intervals. We have also conducted genome wide association studies, whole exome and genome sequencing and have stored DNA and plasma over multiple time points. We now propose to identify those metabolites that are associated with the development of AD and that reflect changes in disease severity over time and how they interact with environmental factors. The strength of our study lies in its ability to investigate changes in the metabolome among a group of individuals from different ethnic and racial backgrounds that have been genetically characterized. Blood is readily available as a means for repeated measures augmenting the precision of individualized analyses particularly when completed in a genetically characterized multi-ethnic cohort. We propose a genetically driven, metabolomics profile analyses from plasma to investigate endogenous metabolites related to AD and exogenous metabolites related to environmental/lifestyle exposures associated with AD. The planned study will provide a major opportunity to add deeper phenotyping using metabolomics to a genetically characterized, multi-ethnic cohort residing in an urban community, which in turn, should clarify the underlying mechanisms linking to genetic and environmental pathways leading to AD.

抽象的 代谢物反映了人类的动态，定性和定量变化，并提供了功能 评估有或没有疾病的个体的生理状态。代谢组代表 基因组的表型与基础生化层之间的最接近联系。在人体中 代谢在代谢过程中的化学转化是对遗传和环境因素的反应 疾病导致疾病或体内变化的因果途径。人类代谢组 在阿尔茨海默氏病（AD）中进行了研究 族裔群体数量有限，几乎没有或没有并发的遗传分析。华盛顿高地， Inwood哥伦比亚老化项目是一个多种族的队列，已收集临床数据和生物资源 几年来，目的是确定AD的环境和遗传危险因素和原因。这 队列非常适合该项目，因为23％是非西班牙裔白人，29％是非裔美国人， 48％是加勒比西班牙裔，并且由于使用经过验证，因此损失至关重 参与者和线人的电话采访。我们进行了医学和神经系统 考试，认知评估和捕获的环境/生活方式风险和保护因素 纵向调查以18个月的间隔进行。我们还进行了广泛的基因组关联研究， 整个外显子组和基因组测序，并在多个时间点上存储了DNA和血浆。我们现在 建议识别与AD发展相关的代谢产物，并反映变化 随着时间的流逝，疾病的严重程度以及它们如何与环境因素相互作用。我们研究的优势在于 它有能力研究来自不同种族和种族的一组个人中代谢组的变化 遗传表征的背景。血液很容易作为重复的手段 衡量个性分析的精度，特别是在遗传上完成的精度 多民族队列的特征。我们提出了来自血浆的基因驱动的代谢组学分析 研究与AD和外源代谢产物有关的内源代谢产物 与AD相关的环境/生活方式暴露。计划的研究将为添加一个主要的机会 使用代谢组学对遗传特征的多种族队列的更深型表型居住在城市中 反过来，社区应阐明与遗传和环境相关的潜在机制 通向广告的途径。