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

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 far<sup>1</sup>, 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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Publication Details

Journal
Nature
Published
2025-06-18
DOI
https://doi.org/10.1038/s41586-025-09083-y
Citations
29
Primary Topic
Stress Responses and Cortisol
Type
article
Field-Weighted Citation Impact
32.27
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article

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

Daniel F. Levey, Matthew J. Girgenti, Che-Yu Lee, Douglas E. Williamson et al.
29 citations
Nature
Stress Responses and Cortisol
32.27
article

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

Daniel F. Levey, Matthew J. Girgenti, Che-Yu Lee, Douglas E. Williamson, P. J. Michael Deans, Nenad Šestan, Ahyeon Hwang, Matthew J. Friedman, Bertrand R. Huber, Alexa‐Nicole Sliby, Xiangyu Zhang, Yingxin Lin, Shushrruth Sai Srinivasan, Alicia Che, Joel Gelernter, Jill R. Glausier, Paul E. Holtzheimer, Ziheng Duan, Ke Xu, Siwei Xu, John Harrison Krystal, Jensine Coudriet, Mario Škarica, Keith A. Young, Kristen Brennand, Hongyu Zhao, Dianne A. Cruz, Lin Lin, David A. Lewis, Min Wu, Yi Dai, Jing Zhang, Jiawei Wang, Hongyu Li, Tuan Nguyen, Rosemarie Terwilliger
article en
29 citations

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 far<sup>1</sup>, 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.

NatureVol. 643(8072)
Dartmouth College (US), Boston University (US), United States Department of Veterans Affairs (US), University of Miami (US), Uniformed Services University of the Health Sciences (US), University of Pittsburgh (US), University of California, Irvine (US), VA Boston Healthcare System (US), Yale University (US), National Center for PTSD (US), Central Texas Veterans Health Care System (US), Duke Medical Center (US), Dr. John T. Macdonald Foundation (US), Duke University Hospital (US), National Center for Post Traumatic Stress Disorder (US), Texas A&M University (US), Bryan College (US)
Openalex Percentile: Top 0%
Stress Responses and Cortisol
32.27
DOIOpen Access PDFOpenAlex
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