Statistical Methods for Epigenetic Mediation of Exposure-response Relations

描述（由申请人提供）：现已明确，DNA甲基化和组蛋白修饰等表观遗传现象在基因表达中发挥着重要作用，表观遗传状态的改变可以影响许多疾病的风险。然而，环境因素、体质基因型及其在决定表观遗传状态中的相互作用的研究较少，特别是表观遗传学作为环境暴露和疾病之间中介的潜力。多项证据还表明，某些环境暴露可能会对后代的健康结果产生影响。该提案有两个广泛的方法学目标，即开发统计方法（1）评估表观遗传学在介导个体内暴露-反应关系中的作用，以及（2）评估其在介导暴露的跨代效应中的作用。对于第一个目标，我们将（目标 1a）开发一个灵活的测量误差框架，该框架可以适应暴露和甲基化随时间的变化，并将其与各种类型的结果（二元、连续、纵向、审查事件时间）相关联，并且（目标 1b）开发总结复杂甲基化谱的方法，并将这些谱与表观遗传状态（环境和遗传）的决定因素和疾病风险联系起来。对于第二个目标，我们将开发一种传递不平衡测试的变体，扩展给定基因座的基因型以包括表观遗传标记，从而允许以非孟德尔方式从亲本传递这些标记。父母和后代的甲基化状态将被视为潜在变量，是他们自己和/或他们各自父母暴露的函数。这些方法的统计性能将通过计算机模拟进行研究。我们将把这些方法应用到儿童健康研究 (CHS) 的不同参与者亚组中，该研究是一项长期队列研究，研究空气污染和其他暴露（如子宫内和环境烟草烟雾）对 12,000 名学童的慢性影响，他们的 DNA 可用于全局和位点特异性甲基化测定；这些包括用于目标 1 纵向分析的新生儿血斑和后来的口腔细胞，以及用于目标 2 的包含祖母吸烟数据的完整三重奏。我们的目标是开发可广泛适用于环境表观遗传学研究的通用方法，仅使用 CHS 的数据作为动机和说明。例如，我们预计这些方法可用于分析国家儿童研究三代子样本的表观遗传数据。 公共健康相关性：表观遗传学是指在不改变其潜在 DNA 序列的情况下影响基因表达的各种变化，包括 DNA 甲基化、组蛋白改变、小非编码 RNA 等。尽管有大量证据表明它们在许多疾病过程中的作用，但这些表观遗传变化的环境决定因素尚未得到充分研究，而且人们对它们在介导暴露反应关系或暴露效应跨代传播中的作用知之甚少。该项目旨在开发创新的统计方法，为流行病学调查人员提供解决这些问题的工具。与 DNA 突变不同，表观遗传变化可能是可逆的，例如，通过膳食补充甲基供体或其他药物，为基于人群的干预措施提供了可能性，以防止不利的环境暴露。

DESCRIPTION (provided by applicant): It is now well established that epigenetic phenomena such as DNA methylation and histone modifications play an important role in gene expression, and alterations in epigenetic states can affect the risk of many diseases. The role of environmental factors, constitutional genotype, and their interactions in determining epigenetic states has been less well studied, however, particularly the potential for epigenetics to serve as a mediator between environmental exposures and disease. Several lines of evidence also suggest that certain environmental exposures can have effects on health outcomes in subsequent generations. This proposal has two broad methodological aims, to develop statistical methods (1) to assess the role of epigenetics in mediating exposure-response relationships within an individual, and (2) to assess its role in mediating transgenerational effects of exposure. For the first of these we will (aim 1a) develop a flexible measurement error framework that can accommodate variation in exposure and methylation over time and relate it to a variety of types of outcomes (binary, continuous, longitudinal, censored time-to-event) and (aim 1b) develop ways of summarizing complex methylation profiles and relating these profiles to both determinants of epigenetic status (environmental and genetic) and to the risk of disease. For the second aim, we will develop a variant of the transmission-disequilibrium test, extending genotypes at a given locus to include epigenetic mark, allowing for transmission of these marks from either parent in a non-Mendelian fashion. The methylation status of parents and offspring will be treated as latent variables that are functions of their own and/or their respective parents' exposures. The statistical performance of these methods will be studied by computer simulation. We will apply these methods to various subsets of participants in the Children's Health Study (CHS) - a long-term cohort study of the chronic effects of air pollution and other exposures like in utero and environmental tobacco smoke in 12,000 school children - for whom DNA are available for global and locus- specific methylation assays; these include neonatal blood spot and later buccal cells for the longitudinal analysis in aim 1 and complete trios with grandmaternal smoking data for aim 2. Our goal is to develop generalizable methodology that will be broadly applicable to studies of environmental epigenetics, using data from the CHS simply as motivation and illustration. For example, we anticipate that these methods could be useful for the analysis of epigenetic data from three-generation subsamples from the National Children's Study. PUBLIC HEALTH RELEVANCE: Epigenetics refers to various changes that can affect the expression of genes without altering their underlying DNA sequence, including DNA methylation, histone alterations, small non-coding RNAs, etc. Despite abundant evidence of their role in many disease processes, the environmental determinants of these epigenetic changes have not been as well studied and little is little known about their role in mediating exposure-response relationships or transmission of exposure effects across generations. This project aims to develop innovative statistical methods to provide epidemiologic investigators with tools for addressing these questions. Unlike DNA mutations, epigenetic changes are potentially reversible, for example, through dietary supplementation with methyl donors or other agents, opening the possibility for population-based interventions to protect against adverse environmental exposures.