Abstract

Background

Negative life experiences (NLE) increase the risk for externalizing (EB) and internalizing (IB) behaviors in adolescence and adult psychopathology. DNA methylation (DNAm) associated with behavioral problems may reflect this risk and long-lasting effects of NLE.

Methods

To identify consistent associations between blood DNAm and EB or IB across adolescence, we conducted longitudinal epigenome-wide association studies (EWAS) using data from the IMAGEN cohort, collected at ages 14 and 19 (n=506). Significant findings were validated in a separate sub-sample (n=823). Methylation risk scores (MRS) were generated by 10-fold cross validation and further tested for their associations with grey matter volumes (GMV) and NLE.

Results

No significant findings were obtained for the IB-EWAS. The EB-EWAS identified a genome-wide significant locus in a gene linked to ADHD (IQSEC1, cg01460382; p=1.26e-08). Other most significant CpG sites were near ADHD-related genes and

enriched for genes regulating TNF and IFN- γ signaling, highlighting relevance the

EB-EWAS findings for ADHD. Analyses with the EB MRS (eMRS) suggested that it was partly reflected comorbidity with IB in late adolescence. Specific to EB, eMRS correlated with smaller GMV in medial orbitofrontal and anterior/middle cingulate cortices, brain regions known to associate with ADHD and conduct problems. Longitudinal mediation analyses indicated that EB-related DNAm were more likely the outcomes of problematic behaviors accentuated by negative life experiences, and less likely the epigenetic bases of such behaviors.

Conclusions

Our findings suggest novel epigenetic mechanisms through which negative life events and their short and longer-term effects on behavior may contribute to ADHD.

*Full text link: https://www.sciencedirect.com/science/article/abs/pii/S0006322322013567