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

摘要 Metabolism反映了人类的动态，质和量的变化，并提供了一个功能 评估患有和未患有疾病的个体的生理状态。代谢组代表了 表型和基因组的基础生化层之间的最密切联系。在人体内， 代谢物在代谢过程中响应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。人类的代谢组 在阿尔茨海默病（AD）中进行了少量的横断面和纵向研究 种族群体数量有限，很少或没有同时进行的遗传分析。华盛顿高地， Inwood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，其目标是确定AD的环境和遗传风险因素和原因。的 队列非常适合这个项目，因为23%是非西班牙裔白人，29%是非洲裔美国人， 48%是加勒比海西班牙裔，由于使用了经过验证的 电话采访参与者和举报人。我们已经进行了医学和神经学检查 检查，认知评估和捕获的环境/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，并已存储了多个时间点的DNA和血浆。我们现在 我建议确定那些与AD的发展相关的代谢物，并反映这些代谢物的变化。 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种族和种族的一组个体的代谢组学变化 有着遗传特征的背景。血液很容易作为一种手段， 增加个体化分析精确度的措施，特别是在基因分析中完成时， 多民族群体的特点。我们提出了一个基因驱动的，代谢组学分析，从血浆 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机会， 使用代谢组学对居住在城市的遗传特征的多种族队列进行更深入的表型分析， 社区，这反过来又应该澄清与遗传和环境有关的潜在机制， 导致AD的途径

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.