Cross-species glucocorticoid-sensitive hippocampal gene network: developing a polygenic score associated with susceptibility to psychiatric conditions in response to adversity in humans
The risk for psychiatric disorders is strongly affected by environmental stressors. The underlying mechanisms are inevitably multifactorial still not fully understood. Glucocorticoids (GCs), which are prominent stress mediators that affect transcriptional activity and brain morphology, are implicated in the pathophysiology of multiple forms of psychopathology.  The challenge is that of establishing the relevance of GC-related transcriptional effects for stress-related psychopathology in humans.  We addressed this issue by generating gene expression data from hippocampal dentate gyrus from macaques and rats to identify clusters of co-expressed genes sensitive to GC exposure as the basis for a biologically-informed polygenic risk score (ePRS) to investigate neuropsychiatric outcomes in humans exposed to early life adversity. We used RNA-sequencing data to identify a cluster of GC-responsive genes co-expressed in the posterior dentate gyrus (pDG) of female Cynomologus monkeys and preserved in the rat model with the homologous region (the dorsal DG).  In total 11395 SNPs derived from these genes (507 genes) were used to create an ePRS to explore the interaction with early life adversity on psychiatric phenotypes in human cohorts using the UK Biobank Resource and ALSPAC data sets. The biologically-informed ePRS significantly predicted psychotic behavior in adversity-exposed females as well as variation in brain volume.  These findings reveal that GC exposure influences a specific group of genes in pDG, largely enriched for transcription processes and pathways related to development activity. Variations in the expression of this gene network can be used in a translational manner to predict risk for neuropsychiatric conditions and brain volume alterations after early stress exposure. These results highlight the importance of hippocampal GC-related transcriptional activity as a mediator for the effects of early life adversity on mental health outcomes. Overall design: RNA sequencing of brain regions in female macaques exposed to glucocorticoids and controls