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Unraveling the cell-type-specific molecular pathways of PTSD: integrating GWAS with brain genomic profiling and in vitro modeling

Neuropsychopharmacology volume 49, pages 303–304 (2024)Cite this article

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Brain genomic profiling, e.g., a bulk transcriptomic study on postmortem cortical tissue [2], uncovered global and sex-specific molecular signatures of PTSD including differentially expressed interneuron markers (ELFN1) and inflammation- and GC-related genes as key drivers of disease-associated networks (Fig. 1B) with moderate to low overlap with MDD. However, cell-type specificity in these analyses relied on inference, underlining the need for single-cell genomic approaches. The first single-nucleus RNA-sequencing study in PTSD showed excitatory and inhibitory neurons’ transcriptomic changes in the dorsolateral prefrontal cortex associated with PTSD, involving dysregulation of immune, mitochondrial and GC-signaling pathways (Fig. 1B) [3]. Genes in the 17q21.31 locus (ARL17B, LINC02210-CRHR1, LRRC37A2), and other GC-regulated genes (SLC16A6, TAF1C) showed prominent cell-type-specific expression alterations. PTSD and MDD findings were more distinct at the cell type compared to the bulk-tissue level, while PTSD results showed the highest replication rate. While valuable for understanding PTSD’s molecular pathophysiology, these studies are limited to describing the “end-stage” of the disease as the temporal trajectories and relative contributions of genetic and environmental effects (stress exposures, clinical dimensions, comorbidities, medications) cannot be statistically deconvoluted.

IPSC-derived cells exposed to stress agents can model “stress in a dish”, capturing both genetic and environmental contributors of the maladaptive stress response (Fig. 1C). Activating the GC-receptor in iPSC-derived neurons using a specific GC-agonist (dexamethasone) induced transcriptomic changes that positively correlated with the neuronal PTSD-signatures and negatively with the MDD-signatures [3]. This showed the relevance of the in vitro stress paradigm for both diseases while confirming the directional differences in their GC regulation. In more complex cellular systems, e.g., iPSC-derived cerebral organoids, cell-type-specific responses to GCs have been also characterized. While transcriptomic changes were observed across cell types, only the neuronal signatures were relevant to neuropsychiatric risk, supporting the significant impact of GC-dysregulation on neuronal-related events [4]. Finally, the preserved PTSD-related genetic background of iPSC-derived lines (proxied by diagnosis) heightened the transcriptomic response to GCs and the alterations overlapped with developmental and adult psychiatric disorders (incl. PTSD)-associated genes [5].

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Fig. 1: Continuum of genomic studies of PTSD: from GWAS to brain and cell studies.

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Funding

This work was supported by NIMH (grants P50-MH115874, R01-MH117292, R01 R01-MH10659, and R21-MH121909). NPD was supported by 2015 and 2018 NARSAD Young Investigator grants from the Brain and Behavior Research Foundation, a Jonathan Edward Brooking mental health research fellowship from McLean Hospital, and a KL2 award from Harvard Catalyst/Harvard Clinical and Translational Science Center (NCATS KL2TR002542, UL1TR002541).

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Authors and Affiliations

  1. McLean Hospital, Belmont, MA, USA

    Artemis Iatrou & Nikolaos P. Daskalakis

  2. Department of Psychiatry, Harvard Medical School, Boston, MA, USA

    Artemis Iatrou & Nikolaos P. Daskalakis

  3. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Artemis Iatrou & Nikolaos P. Daskalakis

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  1. Artemis Iatrou
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AI and NPD drafted and edited the hot topic commentary, prepared the figure, and approved of the final version.

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Correspondence to Nikolaos P. Daskalakis.

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NPD has served on scientific advisory boards for BioVie Pharma, Circular Genomics and Sentio Solutions for unrelated work. All authors declare no competing interests.

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Iatrou, A., Daskalakis, N.P. Unraveling the cell-type-specific molecular pathways of PTSD: integrating GWAS with brain genomic profiling and in vitro modeling. Neuropsychopharmacol. 49, 303–304 (2024). https://doi.org/10.1038/s41386-023-01698-x

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