Statistical Methods for Epigenetic Mediation of Exposure-response Relations

描述（由申请人提供）：现在已经确定表观遗传现象，如DNA甲基化和组蛋白修饰在基因表达中起重要作用，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、体质基因型及其相互作用在决定表观遗传状态中的作用尚未得到充分研究，特别是表观遗传学作为环境暴露与疾病之间的中介的潜力。一些证据还表明，某些环境暴露可能对后代的健康结果产生影响。本提案有两个广泛的方法论目标，即发展统计方法(1)评估表观遗传学在个体内介导暴露-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。对于其中的第一个，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、审查时间到事件）联系起来，（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的决定因素（环境和遗传）和疾病风险联系起来。对于第二个目标，我们将开发一种遗传不平衡测试的变体，将给定位点的基因型扩展到包括表观遗传标记，允许这些标记以非孟德尔方式从亲本传递。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功能。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于儿童健康研究（CHS）的不同亚群参与者，这是一项长期队列研究，研究空气污染和其他暴露（如子宫内和环境中的烟草烟雾）对12,000名学龄儿童的慢性影响，这些儿童的DNA可用于全球和位点特异性甲基化分析；这些包括新生儿血斑和后来的颊细胞的纵向分析，在目标1和完整的三人组与祖母吸烟数据的目标2。我们的目标是开发可广泛应用于环境表观遗传学研究的可推广的方法，使用CHS数据简单地作为动机和说明。例如，我们预计这些方法可以用于分析来自国家儿童研究的三代子样本的表观遗传数据。

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.