Mismatched Prenatal and Postnatal Maternal Depressive Symptoms and Child Behaviours: A Sex-Dependent Role for NR3C1 DNA Methylation in the Wirral Child Health and Development Study

Evolutionary hypotheses predict that male fetuses are more vulnerable to poor maternal conditions (Sex-biased Maternal Investment), but female fetuses are at greater risk of glucocorticoid-mediated disorders where there is a mismatch between fetal and postnatal environments (Predictive Adaptive Response). Self-reported prenatal and postnatal depression and maternal report of child anxious-depressed symptoms at 2.5, 3.5 and 5.0 years were obtained from an ‘extensive’ sample of first-time mothers (N = 794). Salivary NR3C1 1-F promoter methylation was assayed at 14 months in an ‘intensive’ subsample (n = 176) and stratified by psychosocial risk. Generalised structural equation models were fitted and estimated by maximum likelihood to allow the inclusion of participants from both intensive and extensive samples. Postnatal depression was associated with NR3C1 methylation and anxious-depressed symptoms in daughters of mothers with low prenatal depression (prenatal-postnatal depression interaction for methylation, p < 0.001; for child symptoms, p = 0.011). In girls, NR3C1 methylation mediated the association between maternal depression and child anxious-depressed symptoms. The effects were greater in girls than boys: the test of sex differences in the effect of the prenatal-postnatal depression interaction on both outcomes gave X(2) (2) = 5.95 (p = 0.051). This was the first human study to show that epigenetic and early behavioural outcomes may arise through different mechanisms in males and females.