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

Ahyeon Hwang, Mario Skarica, Siwei Xu, Jensine Coudriet, Che Yu Lee, Lin Lin, Rosemarie Terwilliger, Alexa-Nicole Sliby, Jiawei Wang, Tuan Nguyen, Hongyu Li, Min Wu, Yi Dai, Ziheng Duan, Shushrruth Sai Srinivasan, Xiangyu Zhang, Yingxin Lin, Dianne Cruz, P. J. Michael Deans, Bertrand R. Huber, Daniel Levey, Jill R. Glausier, David A. Lewis, Joel Gelernter, Paul E. Holtzheimer, Matthew J. Friedman, Mark Gerstein, Nenad Sestan, Kristen J. Brennand, Ke Xu, Hongyu Zhao, John H. Krystal, Keith A. Young, Douglas E. Williamson, Alicia Che, Jing Zhang () and Matthew J. Girgenti ()
Additional contact information
Ahyeon Hwang: University of California Irvine
Mario Skarica: Yale University School of Medicine
Siwei Xu: University of California Irvine
Jensine Coudriet: Yale University School of Medicine
Che Yu Lee: University of California Irvine
Lin Lin: Yale University School of Medicine
Rosemarie Terwilliger: Yale University School of Medicine
Alexa-Nicole Sliby: Yale University School of Medicine
Jiawei Wang: Yale University School of Medicine
Tuan Nguyen: Yale University School of Medicine
Hongyu Li: Yale University School of Medicine
Min Wu: Yale University School of Medicine
Yi Dai: University of California Irvine
Ziheng Duan: University of California Irvine
Shushrruth Sai Srinivasan: University of California Irvine
Xiangyu Zhang: Yale University School of Public Health
Yingxin Lin: Yale University School of Public Health
Dianne Cruz: Duke University Medical Center
P. J. Michael Deans: Yale University School of Medicine
Bertrand R. Huber: US Department of Veterans Affairs
Daniel Levey: Yale University School of Medicine
Jill R. Glausier: University of Pittsburgh School of Medicine
David A. Lewis: University of Pittsburgh School of Medicine
Joel Gelernter: Yale University School of Medicine
Paul E. Holtzheimer: US Department of Veterans Affairs
Matthew J. Friedman: US Department of Veterans Affairs
Mark Gerstein: Yale University
Nenad Sestan: Yale School of Medicine
Kristen J. Brennand: Yale University School of Medicine
Ke Xu: Yale University School of Medicine
Hongyu Zhao: Yale University School of Public Health
John H. Krystal: Yale University School of Medicine
Keith A. Young: Research Service
Douglas E. Williamson: Duke University Medical Center
Alicia Che: Yale University School of Medicine
Jing Zhang: University of California Irvine
Matthew J. Girgenti: Yale University School of Medicine

Nature, 2025, vol. 643, issue 8072, 744-754

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41586-025-09083-y

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