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.

摘要