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 该建议旨在了解社会经济地位（SES）之间相互作用的影响 基因型以及对表观遗传年龄加速和认知能力下降或认知能力下降的健康行为或 阿尔茨海默氏病。在主要导师Sharon Kardia博士的指导下，培训和研究计划 将建立在施密茨博士在健康经济学和遗传流行病学方面的专业知识的基础上，为她做好准备 将社会科学，遗传学和表观遗传学纳入衰老研究的独立职业。 PI会 在密歇根大学的公共卫生学院进行表观遗传学培训计划 在（1）表观基因组生物学，（2）生物信息学及相关一般一般中提高她的知识和技能 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健康的大量表观基因组数据 和退休研究（HRS）（n = 4,000），以构建全血的DNAM年龄的度量并测试 与已知的遗传，社会和行为机制的衰老和认知下降或认知下降或行为机制的关联或 阿尔茨海默氏病。显示DNAM年龄以高准确性预测年龄，研究已连接 DNAM年龄和年龄年龄之间的正偏差（即表观遗传年龄加速（AGE）） 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衰老中起作用。 但是，很少有研究研究了AGE和SES之间的途径，迄今为止，尚无研究评估。 Age和SE之间的关系是否受遗传影响调节或由风险健康介导 行为。这项工作是基于Schmitz博士先前使用全基因组多基因分数的HRS研究 （PGSS）和社会环境的客观衡量基因环境的影响 关于身体健康和老年认知功能的相互作用。 在K99阶段，Schmitz博士将在HRS中构建DNAM年龄的度量以测试 年与灾难，风险的健康行为和人口特征之间的关联 使用纵向适度介导方法。在R00阶段，Schmitz博士将合并PGSS 进行分析以评估遗传改善教育程度或认知是否适度 SES，gage和随后在痴呆症的认知功能和事件的下降或随后的关系之间的关系 阿尔茨海默氏病。比较分析将在非洲裔美国人的超级样本中进行（nൎ1,000）。 R00研究将采用仪器变量（IV）和动态面板方法来提出更强的主张 考虑休闲。按照这些分析，将在多种族中进行重复的重复 具有可比的遗传，表观遗传和社会数据的人群。该研究计划的结果可能 阐明了支撑SES年道形梯度的特定社会和生物学机制。