Epigenetic Pathways to Conduct Problem Trajectories: Early environmental Risks

描述（由申请人提供）：有早发性行为问题的青少年在社区犯罪中占很大比例，是社会的主要成本（Moffitt, 2006）。最近的研究强调，在早期出现行为问题的青少年中，至少有50%的人在发展后期不会继续出现高水平的行为问题（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提出了挑战。来自双胞胎和基因型研究的有力证据表明，遗传因素和环境因素都与行为问题的风险有关。迄今为止，这类测试主要侧重于基因-环境相互作用的研究，由此表明，具有不同易感基因变体的个体对特定环境风险的易感性是不同的（如统计相互作用测试所证明的）。

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. PUBLIC HEALTH RELEVANCE: A central public health issue involves the provision of evidence-based preventive interventions to reduce youth conduct problems. To this end, a critical enquiry has been about the identification of youth at risk for an early onset of conduct problems; i.e., those most likely to persist in antisocial behaviors across the life course. This application offers an important opportunity to empirically examine epigenetic processes - from birth to late-childhood - that may differentiate heterogeneity in early onset conduct problems (i.e., those who persist and those who desist).