Sex Differences in the Interaction of Epigenetic Risk and Trajectories of Default Mode Limbic Network Integration Predicting Childhood Anxiety

Background Anxiety symptoms often emerge in early development and are more prevalent in females than in males. DNA methylation (DNAm) of stress-related genes at birth may encode susceptibility for anxiety; however, effects may depend on sex and maturation of neural systems involved in self-reference (default mode network; DMN) and attentional-emotional processing (dorsal attention network; DAN). We examined whether DNAm at birth interacts with sex and trajectories of DMN-limbic and DAN-limbic network integration to predict anxiety in early adolescence. Methods Participants were children from the Growing Up in Singapore Towards healthy Outcomes (GUSTO) study (N = 97). DNAm was assayed from cord blood (126 CpG sites) and reduced using principal component analysis. Network integration was derived from resting-state fMRI data at ages 4.5, 6, 7.5, and 10.5 years. Trajectories of DMN-limbic and DAN-limbic network integration were estimated using mixed-effects modeling. Anxiety symptoms were assessed at 13 years using the Multidimensional Anxiety Scale for Children. Regression models tested interactions among DNAm, sex, and trajectories of network integration predicting anxiety. Results A significant three-way interaction of DNAm, sex, and trajectories of DMN-limbic network integration predicted anxiety symptoms (B = 0.56, SE = 0.24, p=.022). Greater DNAm at birth predicted lower anxiety in males with slower increases in DMN-limbic network integration (B=-0.16, SE = 0.25, p=.021). No significant associations were found for females at any level of network integration or for males with faster increases in DMN-limbic network integration. DAN-limbic network integration had no moderation effects. Conclusions Sex-specific interactions with DNAm at birth and DMN-limbic network integration trajectories may confer protection against anxiety in early adolescence.