The first challenge in epigenetic studies of psychopathology is the specification of causal models consistent with hypotheses about how epigenetic modifications may contribute to the production of the phenotypes of interest. Causal models are heuristics that formalize our thinking about the nature, directionality, and temporality of hypothesized relationships between covariates in population data.[26] In forcing us to formalize our hypotheses prior to analysis, these models help us articulate our research questions in light of current knowledge, as well as the limitations of our data. While causal models are implicit in epigenetic studies, they are rarely formalized. Rather than test formal hypotheses, therefore, about how epigenetic modification may be associated with either environmental exposures and/or outcomes of interest, existing studies have been limited to exploratory analyses that do not adequately address current questions in the field. As a potential guiding heuristic, we propose a directed acyclic graph for a generalized epigenetic pathway by which an environmental exposure may operate via epigenetic modification to produce an outcome of interest, shown in Figure 1. The graph demonstrates potential mediation and confounding germane to
