Intermediate endophenotypes and epigenetic mechanisms of psychiatric disorders.

Human neuroimaging and epigenetic research stand ready to advance biological psychiatry. Drawing on the concept of imaging genetics, the analysis of associations between human neuroimaging and epigenetic data provides an attractive framework for investigating multi-scale biological mechanisms linking the environment to psychiatric risk and protection. A basic assumption is that environmental stress causes epigenetic changes that lead to alterations in cellular ensembles, which in turn can be measured as changes in brain structure and function using human neuroimaging. However, unlike genotypes, epigenetics varies within individuals, between cell types, or over time, and thus caution is required when inferring the immediacy and directionality of observed associations. In this review, we discuss recent advances and challenges to this methodological framework. Future studies should address causal hypotheses and explain within-individual variance in psychopathology through sophisticated contextualization of observed associations and rigorous analyses of longitudinal data. These advances will be critical for developing a comprehensive understanding of the biological contributions to mental health risk and protection.