The Add Health Epigenome Resource: Life course stressors and epigenomic modifications in adulthood

摘要 种族/民族和社会经济地位的差异存在于一系列心脏代谢和精神疾病中。 成年后的健康结果，并已被追溯到整个生活中暴露于心理社会压力源 当然了表观基因组的发现提供了一个非凡的机会，以确定途径， 心理社会暴露进入人体，造成健康和疾病方面的不平等。然而一个主要 关于生命过程暴露和表观遗传修饰的现有研究的局限性一直缺乏 前瞻性社会和背景数据收集。事实上，大多数现有的社会表观基因组研究 侧重于单一生命阶段的暴露，或仅依赖于生命早期少数指标的回顾性报告 社会经济地位。为了更全面地了解心理社会压力因素影响 表观基因组，这是至关重要的连接丰富的纵向数据与心理社会压力与表观遗传数据 以及健康和疾病的标志。我们提出的研究将检查“非稳态负荷”相关的基因DNA 甲基化（DNAm）和表达相关的生活过程中的心理社会压力，在参与者中， 国家青少年到成人健康纵向研究（添加健康）。具体而言，我们的建议旨在 揭示生命过程中心理社会压力对功能性表观基因组改变的影响，并确定 将心理社会压力源与心理健康状况不佳联系起来的表观基因组桥梁， 美国人群的心脏代谢疾病。我们假设暴露于社会心理压力源 在整个生命过程中，将与非稳态负荷相关的基因DNAm，这些 模式将因种族/民族和性别而显著不同。此外，我们假设生命历程 压力相关的甲基化差异将与心脏代谢和心理健康相关 结果，部分由基因表达介导。我们将通过以下方式来检验这些假设 具体目标：（1）进行DNA检测，并评估年龄，种族/民族，性别和SES之间的差异， 4，200名新增健康参与者;（2）评估生命过程中的心理社会压力因素（如社会经济压力）是否 逆境，创伤）与添加健康参与者中的非稳态负荷基因中的DNAm相关，包括 同胞和双胞胎的子集;和（3）检查非稳态负荷基因DNAm是否与 心脏代谢健康和抑郁症的措施。我们还将评估这些协会是否 是由基因表达介导的。总的来说，我们的建议将提供前所未有的表观遗传资源， 提供给全球科学界，并将确定新的途径， 压力源影响功能和健康相关的DNA在最大的美国国家代表， 关于社会风险对健康影响的种族/民族多样性纵向研究。

Abstract Disparities by race/ethnicity and socioeconomic status exist across a range of cardiometabolic and mental health outcomes in adulthood, and have been traced to exposure to psychosocial stressors across the life course. The discovery of the epigenome provides a remarkable opportunity to identify the pathways by which psychosocial exposures get into the body to produce inequalities in health and disease. However, a major limitation of extant research on life course exposures and epigenetic modifications has been a dearth of prospective social and contextual data collection. Indeed, the majority of existing social epigenomic studies focus on an exposure at a single life stage or rely on retrospective report of only a few indicators of early life socioeconomic status. To more fully understand the ways in which psychosocial stressors influence the epigenome, it is paramount to connect rich longitudinal data on psychosocial stressors with epigenetic data and markers of health and disease. Our proposed research will examine “allostatic load”-related gene DNA methylation (DNAm) and expression relevant to life course psychosocial stressors, among participants in the National Longitudinal Study of Adolescent to Adult Health (Add Health). Specifically, our proposal seeks to uncover the impact of life course psychosocial stressors on functional epigenomic alterations, and to identify the epigenomic bridges that link psychosocial stressors with the emergence of poor mental health and cardiometabolic conditions in the US population. We hypothesize that exposure to psychosocial stressors across the life course, will be associated with allostatic load-related gene DNAm, and that these patterns will vary significantly by race/ethnicity and sex. Moreover, we hypothesize that life course stress-related methylation differences will be associated with cardiometabolic and mental health outcomes, and partially mediated by gene expression. We will test these hypotheses through the following specific aims: (1) Conduct DNAm testing and assess variation by age, race/ethnicity, sex, and SES among 4,200 Add Health participants; (2) Assess whether life course psychosocial stressors (e.g. socioeconomic adversity, trauma) are associated with DNAm in allostatic load genes among Add Health participants, including a subset of siblings and twins; and (3) Examine whether allostatic load gene DNAm is associated with cardiometabolic health and depression measures in adulthood. We will also assess whether these associations are mediated by gene expression. Overall, our proposal will provide an unprecedented epigenetic resource available to the global scientific community, and will identify novel pathways by which life course psychosocial stressors influence functional- and health relevant DNAm in the largest US nationally representative, racially/ethnically-diverse longitudinal study of social exposures on health.