Modeling gene × environment interactions in PTSD using human neurons reveals diagnosis-specific glucocorticoid-induced gene expression
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Oct 20, 2022
- Source ID
- 10.1038/s41593-022-01161-y
Entities
People
- Barry Mccarthy
- Bruce Sun
- Carina Seah
- Changxin Xu
- Christopher J. Hunter
- Daniel Paull
- Dong Woo Shin
- Dorota Moroziewicz
- Frank Desarnaud
- Frederick J. Monsma
- Geoff Buckley-herd
- Gregory Lallos
- Heather N. Bader
- Hector Martinez
- Hongyan Zhou
- Iouri Makotkine
- Janine D. Flory
- Jenna Hall
- Jordan Goldberg
- Kathryn Reggio
- Katie Brenner
- Kristen J. Brennand
- Laura M Huckins
- Lauren Bauer
- Linda M. Bierer
- Matthew Zimmer
- Michael S Breen
- Migle Staniskyte
- Mitali Chattopadhyay
- Nyscf Global Stem Cell Array® Team
- P. J. Michael Deans
- Patrick Fenton
- Paul Mccoy
- Peter Ferrarotto
- Rachel Yehuda
- Rebecca Tibbets
- Reid Otto
- Scott A. Noggle
- Sean Desmarteau
- Selwyn Jacob
- Tom Rusielewicz
- Travis Kroeker
Organizations
- National Institute of Environmental Health Sciences
- National Institute of Mental Health
- United States Department of Defense
- United States Department of Health and Human Services