Third, an irrevocable condition for causal inference is that exposures must precede outcomes in epidemiologic studies.[31] Plausible causal models require explicitly articulated temporal relationships between environmental exposures, epigenetic modifications, and outcomes of interest. However, to this point, the literature in this area, relegated to cross-sectional studies, has measured epigenetic modification concurrently with outcomes of interest, and in the case of post-mortem brain studies, following these outcomes. In this way, it is impossible to disentangle epigenetic modifications that may have resulted from outcomes themselves from those modifications that may have caused them. For example, a recent cross-sectional case-control analysis by Uddin and colleagues contrasted methylation profiles from peripheral blood from a population of adults with a history of depression with those of non-depressed adults.[37] The study suggested differences in methylation profiles in genes involved in brain development and tryptophan metabolism between cases and controls.[37] However, given the cross-sectional design of the study, it is impossible to ascertain the temporality of the relationship between these methylation differences and depression. While it is plausible that these changes are involved in the etiology of
