Gene expression signatures as biomarkers of childhood trauma-related depression
General, Cognitive and Mathematical Psychology
Final Report Abstract
Severe psychosocial adversity in childhood such as exposure to physical or sexual abuse, neglect or institutional deprivation is associated with poor mental health and neuro-developmental difficulties later in life. This raises the question of how the long-lasting health consequences of early adverse environments are sustained, or ´biologically embedded´. It has been suggested that early adversity leads to a programming of molecular systems and related gene expression profiles, resulting in an altered stress response and in differences in the sensitivity of immune genes towards stress signals. The current project was a renewal project and built upon the project „Long-term consequences of childhood adversity: exploring stress responsive molecular pathways and psychobiological intervention models“. One part of the project was to perform additional analyses on the collected data, namely genome-wide DNA methylation analysis, proteomics, and additional analyses of the gene expression data using state-of-the art gene network analysis. Here we show i) that the previously reported mediating role of DNA methylation in the association between childhood adversity and cortisol stress reactivity does not replicate in monocytes. We did, however, identify three differentially methylated regions associated with cortisol stress reactivity, but not with early adversity, providing little support for a strong association between childhood adversity and DNA methylation differences. ii) differential protein expression between the group of adults reporting childhood adversity and the control group. Functional grouping analyses showed that the cluster of differentially expressed proteins mapped to cell energy metabolism and mitochondrial functioning. In line with previous research, our findings indicate mitochondrial functioning as a target for the effects of childhood adversity. iii) co-expression modules with differential activity between the early adversity and control groups were identified. In line with previous findings reporting a pro-inflammatory bias following childhood adversity, one module included genes associated with pro-inflammatory function (hub genes: IL6, TM4SF1, ADAMTS4, CYR61, CCDC3), more strongly expressed in the early adversity group. Another module down-regulated in the early adversity group was related to platelet activation and wound healing (hub genes: GP9, CMTM5, TUBB1, GNG11, PF4), and resembled a co-expression module previously found over-expressed in PTSD-resilient soldiers. The results provide a system-wide and thus more holistic understanding of stress-induced gene expression programs, and potential dysregulations to this complex machinery associated with childhood adversity. The second part of the project investigated a group of in-patients with PTSD and co-morbid depression across a 8-week intervention. Contrary to our hypothesis, we did not identify a childhood adversity-specific transcriptional signature. We did show changes in mRNA expression over the course of therapy. Gene co-expression analysis identified three differentially expressed gene modules pre- vs. post-intervention. Over representation analysis showed that one module was significantly enriched for transcripts involved in defense response to virus, and response to type 1 interferon. These results are in line with a previous study which showed up-regulation of this gene program following intervention, and provide further support that psychotherapeutic intervention can influence immune system gene expression.
