Modeling gene × environment interactions in PTSD using human neurons reveals diagnosis-specific glucocorticoid-induced gene expression
Carina Seah, Michael S. Breen, Tom Rusielewicz, Heather N. Bader, Changxin Xu, Christopher Hunter, Barry McCarthy, P. J. Michael Deans, Mitali Chattopadhyay, Jordan Goldberg, Saunil Dobariya, Frank Désarnaud, Iouri Makotkine, Janine D. Flory, Linda M. Bierer, Migle Staniskyte, NYSCF Global Stem Cell Array® Team, Lauren Bauer, Katie Brenner, Geoff Buckley-Herd, Sean DesMarteau, Patrick Fenton, Peter Ferrarotto, Jenna Hall, Selwyn Jacob, Travis Kroeker, Gregory Lallos, Héctor Martínez, Paul McCoy, Frederick J. Monsma, Dorota Moroziewicz, Reid Otto, Kathryn Reggio, Bruce Sun, Rebecca Tibbets, Dong Woo Shin, Hongyan Zhou, Matthew Zimmer, Scott Noggle, Laura M. Huckins, Daniel Paull, Kristen Brennand, Rachel Yehuda
Abstract
Post-traumatic stress disorder (PTSD) can develop following severe trauma, but the extent to which genetic and environmental risk factors contribute to individual clinical outcomes is unknown. Here, we compared transcriptional responses to hydrocortisone exposure in human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons and peripheral blood mononuclear cells (PBMCs) from combat veterans with PTSD (n = 19 hiPSC and n = 20 PBMC donors) and controls (n = 20 hiPSC and n = 20 PBMC donors). In neurons only, we observed diagnosis-specific glucocorticoid-induced changes in gene expression corresponding with PTSD-specific transcriptomic patterns found in human postmortem brains. We observed glucocorticoid hypersensitivity in PTSD neurons, and identified genes that contribute to this PTSD-dependent glucocorticoid response. We find evidence of a coregulated network of transcription factors that mediates glucocorticoid hyper-responsivity in PTSD. These findings suggest that induced neurons represent a platform for examining the molecular mechanisms underlying PTSD, identifying biomarkers of stress response, and conducting drug screening to identify new therapeutics.