ABSTRACT Neighborhood disadvantage is a potent predictor of youth risk-taking and aggressive antisocial behaviors (ASB). This association with youth ASB emerges early in life and increases over time. Understanding how neighborhood disadvantage leads to youth ASB thus constitutes a critical public health need. To date, however, the biological mechanism(s) through which disadvantage influences youth ASB remain unclear. The proposed R01 will explore methylation as a key biological pathway underlying the association between neighborhood disadvantage and youth ASB. We specifically postulate that neighborhood disadvantage and its social and physical `active ingredients' (e.g., harsh parenting, exposure to community violence, and toxicant exposure) will predict youth ASB via methylomic alterations, and that these associations will persist over any genetic confounds. To examine this possibility, we will generate methylation data from blood and/or saliva at four assessment waves (neonatal, middle childhood, and early and mid-adolescence) in a discovery sample of 500 adolescent twin pairs (1,000 twins) residing in modestly-to-severely disadvantaged neighborhoods. We then propose to replicate the phenotypic associations in an independent sample of 237 singleton youth living in poverty with methylation data from blood and/or saliva at three assessment waves (neonatal, middle childhood, and mid-adolescence). As our final step, we will leverage the focus on twin pairs in our Discovery twin sample to evaluate whether the replicated methylomic associations are environmental and/or genetic in origin. In short, the proposed R01 will not only identify neighborhood-induced methylomic alterations in two independent samples of impoverished youth, but will also illuminate the environmental and/or genetic etiology of those replicated alterations. In this way, we will move the field of social and environmental epigenetics forward in several areas.