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

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).

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BBBP-R (03))
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Freund, Lisa S
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Birkbeck College
United Kingdom
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Barker, Edward D; Cecil, Charlotte A M; Walton, Esther et al. (2018) Inflammation-related epigenetic risk and child and adolescent mental health: A prospective study from pregnancy to middle adolescence. Dev Psychopathol 30:1145-1156
Felix, Janine F; Joubert, Bonnie R; Baccarelli, Andrea A et al. (2018) Cohort Profile: Pregnancy And Childhood Epigenetics (PACE) Consortium. Int J Epidemiol 47:22-23u
Jensen, Sarah K G; Pangelinan, Melissa; Björnholm, Lassi et al. (2018) Associations between prenatal, childhood, and adolescent stress and variations in white-matter properties in young men. Neuroimage 182:389-397
Milaniak, Izabela; Cecil, Charlotte A M; Barker, Edward D et al. (2017) Variation in DNA methylation of the oxytocin receptor gene predicts children's resilience to prenatal stress. Dev Psychopathol 29:1663-1674
Mesirow, Maurissa Sc; Cecil, Charlotte; Maughan, Barbara et al. (2017) Associations between Prenatal and Early Childhood Fish and Processed Food Intake, Conduct Problems, and Co-Occurring Difficulties. J Abnorm Child Psychol 45:1039-1049
Walton, E; Pingault, J-B; Cecil, C A M et al. (2017) Epigenetic profiling of ADHD symptoms trajectories: a prospective, methylome-wide study. Mol Psychiatry 22:250-256
Rijlaarsdam, Jolien; Cecil, Charlotte A M; Walton, Esther et al. (2017) Prenatal unhealthy diet, insulin-like growth factor 2 gene (IGF2) methylation, and attention deficit hyperactivity disorder symptoms in youth with early-onset conduct problems. J Child Psychol Psychiatry 58:19-27
Walton, Esther; Cecil, Charlotte A M; Suderman, Matthew et al. (2017) Longitudinal epigenetic predictors of amygdala:hippocampus volume ratio. J Child Psychol Psychiatry 58:1341-1350
Meehan, Alan J; Maughan, Barbara; Cecil, Charlotte A M et al. (2017) Interpersonal callousness and co-occurring anxiety: Developmental validity of an adolescent taxonomy. J Abnorm Psychol 126:225-236
Cecil, C A M; Walton, E; Smith, R G et al. (2016) DNA methylation and substance-use risk: a prospective, genome-wide study spanning gestation to adolescence. Transl Psychiatry 6:e976

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