Single-cell transcriptomic and chromatin dynamics of the human brain in PTSD

Nature. 2025 Jul;643(8072):744-754. doi: 10.1038/s41586-025-09083-y.

Ahyeon Hwang ^# ¹ ², Mario Skarica ^# ³, Siwei Xu ^# ², Jensine Coudriet ³, Che Yu Lee ², Lin Lin ³, Rosemarie Terwilliger ³, Alexa-Nicole Sliby ³, Jiawei Wang ³, Tuan Nguyen ³, Hongyu Li ³, Min Wu ³, Yi Dai ², Ziheng Duan ², Shushrruth Sai Srinivasan ¹ ², Xiangyu Zhang ⁴, Yingxin Lin ⁴, Dianne Cruz ⁵ ⁶, P J Michael Deans ³, Traumatic Stress Brain Research Group, Bertrand R Huber ⁶, Daniel Levey ³, Jill R Glausier ⁷, David A Lewis ⁷, Joel Gelernter ³ ⁶, Paul E Holtzheimer ⁶ ⁸, Matthew J Friedman ⁶ ⁸, Mark Gerstein ⁹ ¹⁰ ¹¹ ¹², Nenad Sestan ¹³, Kristen J Brennand ³ ¹⁴, Ke Xu ³ ⁶, Hongyu Zhao ⁴, John H Krystal ³ ⁶, Keith A Young ¹⁵ ¹⁶, Douglas E Williamson ⁵ ⁶, Alicia Che ³, Jing Zhang ¹⁷, Matthew J Girgenti ¹⁸ ¹⁹ ²⁰

Affiliations

1 Mathematical, Computational and Systems Biology Program, University of California Irvine, Irvine, CA, USA.
2 Department of Computer Science, University of California Irvine, Irvine, CA, USA.
3 Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
4 Department of Biostatistics, Yale University School of Public Health, New Haven, CT, USA.
5 Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA.
6 National Center for PTSD, US Department of Veterans Affairs, White River Junction, VT, USA.
7 Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
8 Department of Psychiatry, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.
9 Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA.
10 Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA.
11 Department of Computer Science, Yale University, New Haven, CT, USA.
12 Department of Statistics and Data Science, Yale University, New Haven, CT, USA.
13 Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA.
14 Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
15 Central Texas Veterans Health Care System, Research Service, Temple, TX, USA.
16 Department of Psychiatry and Behavioral Sciences, Texas A&M University College of Medicine, Bryan, TX, USA.
17 Mathematical, Computational and Systems Biology Program, University of California Irvine, Irvine, CA, USA. zhang.jing@uci.edu.
18 Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA. matthew.girgenti@yale.edu.
19 National Center for PTSD, US Department of Veterans Affairs, White River Junction, VT, USA. matthew.girgenti@yale.edu.
20 Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA. matthew.girgenti@yale.edu.
# Contributed equally.

PMID: 40533550 DOI: 10.1038/s41586-025-09083-y

Abstract

Post-traumatic stress disorder (PTSD) is a polygenic disorder occurring after extreme trauma exposure. Recent studies have begun to detail the Molecular Biology of PTSD. However, given the array of PTSD-perturbed molecular pathways identified so far¹, it is implausible that a single cell type is responsible. Here we profile the molecular responses in over two million nuclei from the dorsolateral prefrontal cortex of 111 human brains, collected post-mortem from individuals with and without PTSD and major depressive disorder. We identify neuronal and non-neuronal cell-type clusters, gene expression changes and transcriptional regulators, and map the epigenomic regulome of PTSD in a cell-type-specific manner. Our analysis revealed PTSD-associated gene alterations in inhibitory neurons, endothelial cells and microglia and uncovered genes and pathways associated with glucocorticoid signalling, GABAergic transmission and neuroinflammation. We further validated these findings using cell-type-specific spatial transcriptomics, confirming disruption of key genes such as SST and FKBP5. By integrating genetic, transcriptomic and epigenetic data, we uncovered the regulatory mechanisms of credible variants that disrupt PTSD genes, including ELFN1, MAD1L1 and KCNIP4, in a cell-type-specific context. Together, these findings provide a comprehensive characterization of the cell-specific molecular regulatory mechanisms that underlie the persisting effects of traumatic stress response on the human prefrontal cortex.

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