Using a genome-wide approach, we observed no association between neonatal umbilical cord blood DNA methylation and maternal psychiatric diagnosis or clinically significant depressive symptoms. Lack of association can occur due to insufficient power; however, our analysis had > 80% power to detect group differences explaining > 14.5% of variation in methylation at a single CpG site even after applying the conservative Bonferroni correction. Although it is possible that we did not detect more subtle effects due to limited power, our study was well-powered to detect larger effects. This suggests that the previously reported association between maternal psychiatric illness and adverse offspring outcomes may be due to genetic variants that remain undiscovered or to environmental or behavioral factors that do not correspond with DNA methylation changes present at birth.
Our sample was restricted to women with a lifetime history of a mood disorder diagnosis, which may have resulted in a more restricted range of depressive symptoms experienced during pregnancy. Nevertheless, this study failed to support the hypothesis that clinically significant maternal mood disturbance in pregnancy is associated with DNA methylation changes in cord blood. This finding was somewhat unexpected given the results of previous candidate gene studies. Despite having 90–99% power to identify a nominal association with CpG sites in NR3C1
as strong as those previously reported (semi-partial R2
we observed no association (p < 0.05) between methylation of these genes and maternal psychiatric illness or treatment. This disparity may reflect the limitations of candidate gene studies or it may reflect the fact that we did not interrogate the exact CpG sites that were previously studied.
Prenatal exposure to an antidepressant was associated with differential methylation of CpG sites in TNFRSF21
. TNFRSF21, also known as death receptor 6 (DR6), is expressed in both developing neurons25,26
and developing lymphocytes.27,28
Because of its role in apoptosis, it is involved in refinement of neuronal connections during development.25,26,29
Alterations in TNFRSF21
methylation or gene expression influence complex traits ranging from learning and memory and emotional responses to stressful events to cancer.30,31
is a broadly-expressed subunit of nicotinic acetylcholine receptors.32
In addition to its role in nicotine dependence and neurocognitive functioning,33,34
is located in a region of chromosome 8p that is suggested to contribute to psychiatric and neurodegenerative disorders.35
Interestingly, nominal differential methylation of CHRNA2
was recently reported in monozygotic twins discordant for psychosis.36
Though the results of this analysis are statistically significant, the magnitude of methylation differences between those with and without antidepressant exposure is less than 3% for both CpG sites (), which is unlikely to be biologically significant. They would not satisfy a more conservative Bonferroni criterion (p ≤ 1.81 x 10−6) nor would they remain associated under a FDR strategy that adjusted for the number of phenotypes tested. Thus, these results are most likely false positives.
A potential limitation to this study that DNA extracted from whole umbilical cord blood may not reflect changes in relevant tissues within the neonatal central nervous system. However, both stress-responsive substrates such as cortisol and the medications examined in this study cross the placental barrier and are detectable in umbilical cord blood.15,37,38
The study is strengthened by the rich, prospective characterization of the course of psychiatric illness and treatment as well as other environmental exposures throughout pregnancy.
Delineation of the influence of maternal psychiatric illness and treatment on developing fetuses is vital for informing clinical care decisions of pregnant women. The results of this study suggest that there are no large effects of maternal psychiatric illness, depressive symptoms or prenatal antidepressant exposure on neonatal DNA methylation though we cannot rule out subtle effects. The potential role of maternal psychiatric illness and treatment on long-term offspring behavior and neurocognitive development warrants further attention.