Modeling gene x environment interactions in PTSD using glucocorticoid-induced transcriptomics in human neurons

Abstract

Post-traumatic stress disorder (PTSD) results from severe trauma exposure, but the extent to which genetic and epigenetic risk factors impact individual clinical outcomes is unknown. We assessed the impact of genomic differences following glucocorticoid administration by examining the transcriptional profile of human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons and live cultured peripheral blood mononuclear cells from combat veterans with PTSD (n=5) and without PTSD (n=5). This parallel examination in baseline and glucocorticoid-treated conditions resolves cell-type specific and diagnosis-dependent elements of stress response, and permits discrimination of gene expression signals associated with PTSD risk from those induced by stress. Computational analyses revealed neuron-specific glucocorticoid-response expression patterns that were enriched for transcriptomic patterns observed in clinical PTSD samples. PTSD-specific signatures, albeit underpowered, accurately stratify veterans with PTSD relative to combat-exposed controls. Overall, in vitro PTSD and glucocorticoid response signatures in blood and brain cells represent exciting new platforms with which to test the genetic and epigenetic mechanisms underlying PTSD, identify biomarkers of PTSD risk and onset, and conduct drug-screening to identify novel therapeutics to prevent or ameliorate clinical phenotypes.

Modeling gene × environment interactions in PTSD using human neurons reveals diagnosis-specific glucocorticoid-induced gene expression

“…These pilot studies sought to evaluate the transcriptional effects of HCort and DEX on NGN2-neurons, and optimize the length of glucocorticoid treatment and concentrations. Neither quantitative PCR for six glucocorticoid regulatory genes (covering ten concentrations of DEX) nor RNA-seq (covering three concentrations of DEX) revealed significant gene expression differences following 72 h of exposure 87 , consistent with minimal upregulation of FKBP5 mRNA expression following DEX treatment of hiPSC neurons 19 . This is consistent with previous reports of DEX treatment of primary cultures, which found neurons to be significantly less responsive than astrocytes 88 .…”

Convergent impact of schizophrenia risk genes

“…However, there are limitations to this approach. First, it is necessary to test the generalizability of our findings beyond the set of twelve genes chosen here; new CRISPRa and CRISPRi systems use different gRNA scaffold sequences 50,52 , making new bi-directional, combinatorial gene perturbations in the same cell theoretically possible. Second, our CRISPRa analyses are from glutamatergic neurons only, and so do not consider the convergence across cell types or within more complex neuronal circuits.…”

“…Finally, being most like fetal brain cells, hiPSC neurons cannot capture convergence that occurs at the time of symptom onset and thereafter; transcriptional consequences that may affect neurobiology during childhood or adolescence cannot be easily modelled with hiPSC-based platforms. Thus, future investigation to assess how transcriptional convergence differs across gene sets, drug/environmental contexts 52 , brain regions 53 and cell types 54 , developmental timespans 55 , and donor backgrounds 56 will inform the cell-type-specific and context-dependent nature of convergence.…”

Trauma Matters: Integrating Genetic and Environmental Components of PTSD

“…[ 186 ] Additionally, in vitro PTSD and glucocorticoid response signatures in human induced pluripotent stem cell (hiPSC)‐derived glutamatergic neurons and live cultured peripheral blood mononuclear cells represent exciting new platforms with which to test the genetic and epigenetic mechanisms underlying PTSD. [ 187 ]…”

“…[186] Additionally, in vitro PTSD and glucocorticoid response signatures in human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons and live cultured peripheral blood mononuclear cells represent exciting new platforms with which to test the genetic and epigenetic mechanisms underlying PTSD. [187] Last, trauma exposure has been demonstrated to be heritable. Certain personality factors are heritable (i.e., harm avoidance), and can increase/decrease an individual's risk of exposure to TSLEs and subsequent PTSD.…”