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 代谢物反映人体动态、质、量的变化，为人体提供功能 评估有病和无病个体的生理状态。代谢组代表 表型和基因组底层生化层之间最密切的联系。在人体中， 代谢物在新陈代谢过程中因遗传和环境因素而发生化学转化 疾病或疾病导致的体内变化的因果途径。人类代谢组有 在阿尔茨海默病 (AD) 中进行了少量横断面和纵向研究 种族群体数量有限，并且很少或根本没有同时进行的遗传分析。华盛顿高地， 因伍德哥伦比亚老龄化项目是一个多种族队列，收集了临床数据和生物资源 多年来，我们的目标是确定 AD 的环境和遗传风险因素以及原因。这 该群体非常适合该项目，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，而且由于使用经过验证的方法，失访率极低 对参与者和知情人进行电话采访。我们进行了医学和神经学方面的研究 检查、认知评估以及捕获的环境/生活方式风险和保护因素 每隔 18 个月进行一次纵向调查。我们还进行了全基因组关联研究， 全外显子组和基因组测序，并在多个时间点储存了 DNA 和血浆。我们现在 建议确定那些与 AD 发展相关并反映变化的代谢物 随着时间的推移，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 它能够调查来自不同民族和种族的一群人的代谢组变化 已被遗传特征化的背景。血液很容易获得，可作为重复治疗的手段 提高个体化分析精度的措施，特别是在基因分析中完成时 具有多种族特征的队列。我们提出了一种基因驱动的血浆代谢组学分析 研究与AD相关的内源性代谢物和与AD相关的外源性代谢物 与 AD 相关的环境/生活方式暴露。计划中的研究将提供一个重要的机会来增加 使用代谢组学对居住在城市的具有遗传特征的多种族群体进行更深入的表型分析 社区，反过来，应该澄清与遗传和环境相关的潜在机制 导致 AD 的途径。