Life Course Determinants of Epigenetic Age Acceleration and Subsequent Dementia

项目摘要 该提案旨在了解社会经济地位（SES）之间相互作用的影响， 基因型和健康行为对表观遗传年龄加速和认知能力下降的差异， 老年痴呆症在初级导师Sharon卡尔迪亚博士的指导下，培训和研究计划 Schmitz博士在卫生经济学和遗传流行病学方面的专业知识， 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。pi将 在密歇根大学公共卫生学院进行表观遗传学培训， 推进她的知识和技能（1）表观基因组生物学，（2）生物信息学和相关的一般 程序设计，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卫生部的大量表观基因组数据样本， 和退休研究（HRS）（N = 4，000），以构建全血中DNA年龄的测量值，并检测 与已知的衰老和认知能力下降的遗传、社会和行为机制相关，或 老年痴呆症DNA年龄被证明可以很准确地预测年龄，研究表明， DNA年龄和实际年龄之间的正偏差（即表观遗传年龄加速（表观年龄））， 与年龄有关的疾病和死亡率，表明表观遗传过程可能在健康老龄化中发挥作用。 然而，很少有研究调查了抑郁症和SES之间的途径，迄今为止还没有研究评估 年龄和社会经济地位之间的关系是由遗传影响调节还是由危险的健康介导 行为。这项工作建立在Schmitz博士之前使用全基因组多基因评分的HRS研究基础上 （PGSs）和社会环境的客观措施，以检查基因-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，Schmitz博士将在HRS中构建DNAm年龄的测量，以测试 老年人与弱势社会经济地位、危险健康行为和人口统计学特征之间的关联 使用纵向调节-调解方法。在R00阶段，Dr. Schmitz将纳入PGS 分析，以评估是否遗传倾向的教育程度或认知调节， SES、年龄和随后认知功能下降与痴呆或 老年痴呆症将在非裔美国人的超额样本（N = 1，000）中进行比较分析。 R00研究将采用工具变量（IV）和动态面板方法来得出更有力的主张 关于因果关系。在这些分析之后，将在多族裔社区推广主要调查结果， 具有可比的遗传、表观遗传和社会数据的队列。这项研究计划的结果可能 阐明了支持SES死亡率梯度的特定社会和生物机制。

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.