B3972 - The relationship between the timing of prenatal alcohol exposure DNA methylation and depressive symptom trajectories - 17/01/2022

B number: 
Principal applicant name: 
Alexandre Lussier | Massachusetts General Hospital (United States)
Dr. Erin C. Dunn
Title of project: 
The relationship between the timing of prenatal alcohol exposure, DNA methylation, and depressive symptom trajectories
Proposal summary: 

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.

Impact of research: 
Previous reports estimate that 10-15% of children are exposed to alcohol during pregnancy; numbers that are expected to rise due to the increases in alcohol use during the ongoing COVID-19 pandemic. By identifying the causal link between PAE and depression, this research will highlight the importance of PAE as a key modifiable and targetable factor in the prevention of depression. Through this work, we will also identify the molecular mechanisms that drive risk for depression across development and determine the optimal trimesters when interventions can be implemented to reduce the impact of prenatal alcohol exposure on depression risk. Specifically, we will identify a set of epigenetic biomarkers influenced by prenatal alcohol exposure and that predict the manifestation of depressive symptoms across development, as well as determine the trimesters when alcohol is most likely to causally affect these DNAm marks. Ultimately, this work will identify the specific periods when PAE can influence depression, which will help target interventions to the individuals who are at higher risk for early-onset depression.
Date proposal received: 
Thursday, 13 January, 2022
Date proposal approved: 
Monday, 17 January, 2022
Mental health - Psychology, Psychiatry, Cognition, Addiction - e.g. alcohol, illicit drugs, smoking, gambling, etc., Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Mental health, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Computer simulations/modelling/algorithms, Statistical methods, Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., Birth outcomes, Environment - enviromental exposure, pollution, Epigenetics, Genetic epidemiology, Genetics, Mendelian randomisation, Nutrition - breast feeding, diet, Parenting