Statistical Methods for Epigenetic Mediation of Exposure-response Relations

描述（由申请人提供）：现已确定，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影响许多疾病的风险。环境因素的作用，宪法基因型，以及它们之间的相互作用，在确定表观遗传状态的研究较少，但是，特别是表观遗传学作为环境暴露和疾病之间的调解人的潜力。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。该建议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联系起来。（二元、连续、纵向、删失的事件发生时间）和（目标1b）开发总结复杂甲基化图谱的方法，并将这些图谱与表观遗传状态的两个决定因素相关联（环境和遗传）和疾病的风险。对于第二个目标，我们将开发一个变种的传输不平衡测试，扩展基因型在一个给定的基因座，包括表观遗传标记，允许这些标记的传输从任何一个父母在一个非孟德尔的方式。父母和后代的甲基化状态将被视为潜在变量，其是其自身和/或其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于儿童健康研究（CHS）的不同参与者子集-一项关于空气污染和其他暴露（如子宫内和环境烟草烟雾）对12，000名学龄儿童的慢性影响的长期队列研究-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随后的颊细胞，用于aim 1中的纵向分析，以及aim 2中的完整三项与祖母吸烟数据。我们的目标是开发可推广的方法，将广泛适用于环境表观遗传学的研究，从CHS的数据只是作为动机和说明。例如，我们预计，这些方法可能是有用的表观遗传数据的分析，从三代子样本的国家儿童研究。 公共卫生相关性：表观遗传学是指各种可以影响基因表达而不改变其潜在DNA序列的变化，包括DNA甲基化，组蛋白改变，小的非编码RNA等。尽管有大量证据表明它们在许多疾病过程中的作用，这些表观遗传变化的环境决定因素还没有得到很好的研究，关于它们在介导暴露中的作用也知之甚少-反应关系或世代间接触效应的传递。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，表观遗传变化具有潜在的可逆性，例如，通过膳食补充甲基供体或其他试剂，为基于人口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.