Life Course Determinants of Epigenetic Age Acceleration and Subsequent Dementia

表观遗传年龄加速和随后的痴呆的生命历程决定因素

• 批准号: 10001413
• 负责人: Lauren Lucia Schmitz
• 金额: $ 24.88万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10001413
• 关键词: Acceleration; Activities of Daily Living; Adult; Affect; African American; Age; Aging; Alcohol consumption; Alzheimer' s Disease; Behavioral; Behavioral Genetics; Behavioral Mechanisms; Bioinformatics; Biological; Biological Markers; Biology; Blood; Blood Tests; Characteristics; Childhood; Chronology; Cognition; Cognitive; Collection; Cytosine; DNA; DNA Methylation; DNA analysis; Data; Dementia; Disease; Education; Elderly; Environment; Epigenetic Process; Ethnic Origin; Etiology; Gene Expression; Genes; Genetic; Genome; Genotype; Guanine; Health; Health and Retirement Study; Health behavior; Impaired cognition; Incidence; Individual; Individual Differences; Intervention; Joints; Knowledge; Life Cycle Stages; Life Expectancy; Light; Link; Measures; Mediating; Mediation; Memory Loss; Mentors; Methods; Methylation; Michigan; Minority; Modeling; Molecular; Obesity; Occupational Status; Pathway interactions; Phase; Play; Policies; Positioning Attribute; Premature Mortality; Process; Public Health Schools; Quality of life; Race; Regression Analysis; Research; Respondent; Role; Sampling; Schools; Site; Smoking; Social Environment; Social Sciences; Socioeconomic Status; Testing; Time; Tissues; Training; Training Programs; Universities; Weight; Whole Blood; Work; age related; age related cognitive change; career; cognitive function; cohort; comparative; epigenome; epigenomics; gene environment interaction; genetic epidemiology; health data; health disparity; health economics; healthy aging; inorganic phosphate; mortality; physical conditioning; physical inactivity; population based; programs; research study; sex; skills; social; social factors; socioeconomic disadvantage; trait; whole genome

PROJECT ABSTRACT This proposal seeks to understand the impact of interactions between socioeconomic status (SES), genotype, and health behaviors on disparities in epigenetic age acceleration and cognitive decline or Alzheimer's disease. Under the guidance of primary mentor Dr. Sharon Kardia, the training and research plan will build upon Dr. Schmitz's expertise in health economics and genetic epidemiology to prepare her for an independent career that integrates social science, genetics, and epigenetics into aging research. The PI will pursue a program of training in epigenetics at the University of Michigan's School of Public Health that will advance her knowledge and skills in (1) epigenomic biology, (2) bioinformatics and related general programming, and (3) preprocessing and analysis of DNA methylation (DNAm) microarray data. The proposed research plan will capitalize on a large sample of epigenome-wide data from the Health and Retirement Study (HRS) (N=4,000) to construct measures of DNAm age in whole blood and test for associations with known genetic, social, and behavioral mechanisms of aging and cognitive decline or Alzheimer's disease. DNAm age been shown to predict age with high accuracy, and studies have linked positive deviations between DNAm age and chronological age (i.e. epigenetic age acceleration (age)) with age-related diseases and mortality, suggesting that epigenetic processes may play a role in healthy aging. However, few studies have investigated pathways between age and SES, and to date no study has evaluated whether the relationship between age and SES is moderated by genetic influences or mediated by risky health behaviors. This work builds on Dr. Schmitz's prior HRS research that used whole-genome polygenic scores (PGSs) and objective measures of the social environment to examine the effect of gene-environment interactions on physical health and cognitive function at older ages. During the K99 phase, Dr. Schmitz will construct measures of DNAm age in the HRS to test for associations between age and disadvantaged SES, risky health behaviors, and demographic characteristics using longitudinal moderation-mediation methods. During the R00 phase, Dr. Schmitz will incorporate PGSs into the analyses to assess whether genetic propensity for educational attainment or cognition moderates the relationship between SES, age, and subsequent declines in cognitive function and incidence of dementia or Alzheimer's disease. Comparative analyses will be conducted in an African American oversample (Nൎ1,000). R00 research will employ instrumental variables (IV) and dynamic panel methods to draw stronger claims regarding causality. Following these analyses, replication of main findings will be pursued in multi-ethnic cohorts that have comparable genetic, epigenetic, and social data. Results from this research program may shed light on the specific social and biological mechanisms that underpin the SES-mortality gradient.

项目摘要 这项建议旨在了解社会经济地位(SES)和社会经济地位(SES) 表观遗传年龄加速和认知功能减退差异的基因型和健康行为 阿尔茨海默氏症。在初级导师莎伦·卡迪亚博士的指导下，培训和研究计划 将以施密茨博士在卫生经济学和遗传流行病学方面的专业知识为基础，为她的 将社会科学、遗传学和表观遗传学整合到衰老研究中的独立职业。私人侦探将 在密歇根大学公共卫生学院继续进行表观遗传学培训，这将 提高她在(1)表观基因组生物学，(2)生物信息学及相关一般知识和技能方面的知识和技能 编程，以及(3)DNA甲基化(DNaM)微阵列数据的预处理和分析。 拟议的研究计划将利用来自美国卫生署的表观基因组数据的大样本 和退休研究(HRS)(N=4,000)，以构建全血中dNaM年龄的测量并测试 与已知的遗传、社会和行为机制衰老和认知能力下降或 阿尔茨海默氏症。DNaM年龄被证明可以高精度地预测年龄，研究表明 DNaM年龄和年代年龄之间的正偏差(即表观遗传年龄加速(年龄)) 与年龄相关的疾病和死亡率，表明表观遗传过程可能在健康老龄化中发挥作用。 然而，很少有研究调查年龄和自发性硬化症之间的途径，而且到目前为止还没有研究评估 年龄和自发性硬化症之间的关系是由遗传影响调节的还是由危险健康调节的 行为。这项工作建立在施密茨博士之前使用全基因组多基因分数进行的HRS研究的基础上 (PGSS)和客观的社会环境措施来考察基因-环境的影响 老年人身体健康和认知功能的相互作用。 在K99阶段，施密茨博士将在HRS中构建dNaM年龄的测量方法，以测试 年龄与弱势社会经济地位、危险健康行为和人口学特征的关系 采用纵向缓和-调停的方法。在R00阶段，施密茨博士将纳入PGSS 分析以评估受教育程度或认知的遗传倾向是否会影响 自发性硬化症、年龄和随后认知功能下降与痴呆发病率的关系 阿尔茨海默氏症。将在非裔美国人过抽样(Nൎ1,000)中进行比较分析。 R00研究将使用工具变量(IV)和动态面板方法来得出更强有力的主张 关于因果关系。在这些分析之后，将在多民族中重复主要发现 具有可比较的遗传、表观遗传和社会数据的队列。这项研究计划的结果可能 阐明了支撑SES-死亡率梯度的具体社会和生物机制。