Transcriptional evidence of HPA axis dysregulation in adolescent females: Unique contributions of chronic early-life stressor exposure and maternal depression history.

Background: Depression risk increases dramatically for adolescent females following the pubertal transition. Although chronic early-life stressor exposure and a maternal history of depression are established risk factors for depression onset in this population, we know little about the biological mechanisms underlying these associations.

Method: To investigate, we examined how chronic early-life stressor exposure and maternal depression history were associated with stress-related gene expression patterns, using a high-risk family design in 48 psychiatrically healthy adolescent females, 20 of whom had a mother with a lifetime history of depression. Lifetime chronic stressor exposure was assessed using the STRAIN and gene expression patterns were estimated using transcriptional profiling of whole blood.

Results: Consistent with hypotheses, we found that adolescent females with greater chronic stressor exposure had higher NR3C1 expression levels compared to those with less chronic stressor exposure. Additionally, youth with a depressed mother had lower levels of FKBP5 expression compared to those without a depressed mother. Levels of FKBP5 expression, in turn, interacted with chronic stressor exposure to predict NR3C1 expression. Specifically, for those with low chronic stressor exposure, levels of FKBP5 and NR3C1 expression were strongly interrelated, whereas for those with high chronic stressor exposure, NR3C1 expression was high regardless of levels of FKBP5 expression.

Limitations: This study was correlational, the sample size was limited, and additional research is needed to elucidate the underlying mechanisms and predict who subsequently develops depression.

Conclusions: Notwithstanding these limitations, these data indicate that having low FKBP5 expression, alongside high NR3C1 expression, may be a potential preclinical marker of depression risk in adolescent females that warrants additional investigation.