Epigenetic Pathways to Conduct Problem Trajectories: Early Environmental Risks

描述（由申请人提供）：青少年早发性行为问题占社区犯罪的很大比例，是社会的主要成本（Moffitt，2006）。最近的研究强调，在早发性行为问题青年中，至少有50%的人在以后的发展中不会继续存在高水平的行为问题（Barker和Maughan，2009）。早发人群的这种异质性对公共政策和有针对性的早期干预措施构成了挑战。双胞胎和基因型研究都有强有力的证据表明，遗传和环境因素都与行为问题的风险有关。迄今为止，这些测试主要侧重于基因-环境相互作用研究，由此表明，对特定环境风险的脆弱性在具有不同易感基因变体的个体之间存在差异（如统计相互作用测试所证明的那样）。 这种应用程序的重点是检查一个潜在的机制背后的基因与环境的相互作用：基因表达的表观遗传调控。表观遗传学是指基因表达的可逆调节，其发生独立于DNA序列，主要通过DNA甲基化和染色质结构的变化介导。动物模型已经显示出（i）DNA甲基化对早期应激暴露的响应，以及（ii）DNA甲基化可能逆转的关键时期。目前尚不清楚在动物中显示的表观遗传机制是否延伸到人类，并与行为问题的发展有关。因此，对于任何特定类型的立即临床实施，该应用不可避免地是探索性和推测性的。然而，这项工作是必不可少的，以便人类干预和早期干预文献可以通过有关行为发展的生物学假设的进展来了解。该应用程序有三个创新。首先，使用从出生时，7岁和9岁的青年获得的DNA，我们将检查先前显示与行为问题相关的候选基因中DNA甲基化的变化（例如，参与糖皮质激素、肾上腺素能、多巴胺和神经营养系统的基因座），并在全基因组策略内-对基因组的无假设搜索，其可以识别先前未考虑的生物系统的表观遗传调节。第二，我们将审查从酝酿阶段开始的相关环境风险（例如，产前母亲压力，反社会的生活方式，不良的饮食和物质使用），并包括幼儿期（例如，严厉，温暖的养育），和童年后期（例如，父母参与，同伴受害），这可能会影响不同基因甲基化的变化。第三，我们将估计DNA甲基化的变化轨迹，并将这些轨迹与环境压力（产前到儿童晚期）和早发性行为问题轨迹联系起来。两者合计，本申请中提出的研究问题的优势和新奇可以为已发表的纵向行为问题研究增加重要的病因学信息。

DESCRIPTION (provided by applicant): Youth with early-onset conduct problems account for a high proportion of crime within a community and are a major cost to society (Moffitt, 2006). Studies have recently highlighted that within early onset conduct problem youth, at least 50 percent do not continue in high levels of conduct problems later in development (Barker and Maughan, 2009). Such heterogeneity within early onset groups poses challenges for public policy and targeted early interventions. Evidence is robust from both twin and genotype studies that both heritable and environmental factors are implicated in risk for conduct problems. To date, such tests have focused primarily on gene-environment interaction studies, whereby vulnerability to specified environmental risks has been shown to vary (as evidenced by statistical interaction tests) between individuals with differing variants of susceptibility genes. This application focuses on the examination of one potential mechanism behind such gene-environment interplay: the epigenetic regulation of gene expression. Epigenetics refers to the reversible regulation of gene expression, occurring independently of DNA sequence, mediated principally through changes in DNA methylation and chromatin structure. Animal models have shown (i) DNA methylation in response to early stress exposures, and (ii) a critical period in which DNA methylation may be reversed. It is unknown if the epigenetic mechanisms shown in animals extends to humans, and are relevant to the development of conduct problems. Hence, this application is inevitably exploratory and speculative with regard to any specific kind of immediate clinical implementation. Nevertheless, the work is essential so that the human intervention and early intervention literatures can be informed by progress concerning biological hypotheses for behavioral development. This application has three innovations. First, using DNA obtained from youth at birth, age 7 and age 9, we will examine changes in DNA methylation both in Candidate genes previously shown to associate to conduct problems (e.g., loci involved in the glucocorticoid, serotonergic, dopamingeric and neurotrophic systems), and within a whole-genome strategy - a hypothesis-free search of the genome that may identify epigenetic regulation of previously unconsidered biological systems. Second, we will examine relevant environmental risks beginning in gestation (e.g., prenatal maternal stress, antisocial lifestyle, poor diet and substance use), and including early childhood (e.g., harsh, warm parenting), and late-childhood (e.g., parental involvement, peer victimization) that may bear on change in methylation of different genes. Third, we will estimate trajectories of change in DNA methylation, and relate these trajectories to environmental stress (prenatal to late-childhood) and to the early onset conduct problem trajectories. Taken together, the strengths and novelty of the research questions posed in this application could add important etiologic information to published longitudinal conduct problem studies.