Prenatal alcohol exposure (PAE) is a potent risk factor for depression, with several studies showing that moderate levels of PAE can more than double depression risk. However, the biological mechanisms linking alcohol exposure to long-term vulnerability for depression remain poorly understood. One possibility is that PAE reprograms the epigenome through DNA methylation (DNAm), epigenetic modifications that do not change the sequence of the genome, but can alter gene expression. Both animal and human studies suggest that PAE can induce lasting DNAm changes in the brain and periphery, including in blood and buccal epithelial cells, and that these DNAm profiles are associated with disease risk. Despite these known links between PAE, DNAm, and depression, there are three main gaps in the literature.

First, most human epigenetic studies are cross-sectional and cannot evaluate the causal links between PAE, epigenome-wide DNAm, and depression. As such, it remains unknown whether the relationship between PAE and depression is causal, requiring additional genetic and environmental analyses to parse this relationship.

Second, nearly all studies define PAE as any exposure to alcohol between conception and birth, despite recent evidence that the effects of early-life exposures may have vary depending on when they occur. As such, it remains unknown whether there are specific trimesters or sensitive periods when children are more vulnerable, PAE differentially affects DNAm patterns, and prevention efforts might be most effective.

Third, depression can manifest through different time-dependent patterns after its initial onset, varying with regards to symptom levels, recurrence, and length. Given that a single timepoint cannot fully capture this time-dependent variability, we recently harnessed repeated measures of depressive symptoms to characterize a set of unique depressive symptom trajectories across childhood and adolescence (Lussier 2020; Hawrilenko 2020). However, it remains unclear when and how prenatal risk factors, such as alcohol, influence the manifestation of depressive symptoms across development.

As such, we seek to extend our prior work, which focused on sensitive periods for childhood adversity, to further investigate the relationship between prenatal alcohol exposure, DNAm, and depressive symptom trajectories across development. The central hypothesis we will test is that PAE has causal and time-dependent influences on depression heterogeneity across development, with measurable effects on depressive symptom trajectories and epigenetic processes from age 4 to 24.