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

摘要 在一系列心脏代谢和精神疾病患者中，存在种族/民族和社会经济地位的差异 成年后的健康结果，并被追溯到一生中暴露在心理社会应激源中 当然了。表观基因组的发现提供了一个极好的机会来确定 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，一个主要的 现有关于生命过程暴露和表观遗传修饰的研究一直是缺乏的 预期的社会和背景数据收集。事实上，现有的大多数社会表观经济学研究 专注于单一生命阶段的暴露，或依赖于仅有几个早期生命指标的回顾报告 社会经济地位。为了更全面地了解心理社会应激源如何影响 表观基因组，将心理社会应激源的丰富纵向数据与表观遗传学数据联系起来是至关重要的 以及健康和疾病的标志。我们计划进行的研究将检测与“等静负荷”相关的基因DNA。 与生活过程心理社会应激源相关的甲基化(DNaM)和表达 全国青少年到成人健康纵向研究(ADD Health)。具体地说，我们的建议旨在 揭示生活过程中心理社会应激源对功能性表观基因组改变的影响，并确定 表观基因组学桥梁将心理社会应激源与心理健康不良和 美国人群的心脏代谢状况。我们假设暴露在心理社会应激源中 在整个生命过程中，都会与恒定负荷相关的基因dNaM相关，而这些 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 与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检验这些假设 具体目标：(1)进行dNaM测试并评估不同年龄、种族/民族、性别和社会经济状况的差异 增加4,200名健康参与者；(2)评估生命过程中的心理社会应激源(例如社会经济压力) 逆境、创伤)与ADD健康参与者中异位负荷基因中的dNaM相关，包括 兄弟姐妹和双胞胎的子集；以及(3)检查变态负荷基因dNaM是否与 成年后心脏新陈代谢健康和抑郁的测量。我们还将评估这些协会是否 都是通过基因表达来调节的。总体而言，我们的提议将提供前所未有的表观遗传资源 可供全球科学界使用，并将确定生命过程心理社会的新途径 在美国最大的全国代表性地区，应激源影响与功能和健康相关的dNaM， 对健康方面的社会暴露进行种族/族裔多样化的纵向研究。

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.