Stress genomics revisited: gene co-expression analysis identifies molecular signatures associated with childhood...

Childhood adversity is related to an increased risk for psychopathology in adulthood. Altered regulation of stress response systems, as well as the changes in stress-immune interplay have been suggested as potential mechanisms underlying these long-term effects. We have previously shown altered transcriptional responses to acute psychosocial stress in adults reporting the experience of childhood adversity. Here, we extend these analyses using a network approach. We performed a co-expression network analysis of genome-wide mRNA data derived from isolated monocytes, sampled 3 h after stress exposure from healthy adults, who experienced childhood adversity and a matched control group without adverse childhood experiences. Thirteen co-expression modules were identified, of which four modules were enriched for genes related to immune system function. Gene set enrichment analysis showed differential module activity between the early adversity and control group. 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 downregulated 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 post-traumatic stress disorder resilient soldiers. These discovery analysis results provide a system wide and more holistic understanding of gene expression programs associated with childhood adversity. Furthermore, identified hub genes can be used in directed hypothesis testing in future studies.