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Integration of peripheral transcriptomics, genomics, and interactomics following trauma identifies causal genes for symptoms of post-traumatic stress and major depression

Molecular Psychiatry volume 26, pages 3077–3092 (2021)Cite this article

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Abstract

Posttraumatic stress disorder (PTSD) is a debilitating syndrome with substantial morbidity and mortality that occurs in the aftermath of trauma. Symptoms of major depressive disorder (MDD) are also a frequent consequence of trauma exposure. Identifying novel risk markers in the immediate aftermath of trauma is a critical step for the identification of novel biological targets to understand mechanisms of pathophysiology and prevention, as well as the determination of patients most at risk who may benefit from immediate intervention. Our study utilizes a novel approach to computationally integrate blood-based transcriptomics, genomics, and interactomics to understand the development of risk vs. resilience in the months following trauma exposure. In a two-site longitudinal, observational prospective study, we assessed over 10,000 individuals and enrolled >700 subjects in the immediate aftermath of trauma (average 5.3 h post-trauma (range 0.5–12 h)) in the Grady Memorial Hospital (Atlanta) and Jackson Memorial Hospital (Miami) emergency departments. RNA expression data and 6-month follow-up data were available for 366 individuals, while genotype, transcriptome, and phenotype data were available for 297 patients. To maximize our power and understanding of genes and pathways that predict risk vs. resilience, we utilized a set-cover approach to capture fluctuations of gene expression of PTSD or depression-converting patients and non-converting trauma-exposed controls to find representative sets of disease-relevant dysregulated genes. We annotated such genes with their corresponding expression quantitative trait loci and applied a variant of a current flow algorithm to identify genes that potentially were causal for the observed dysregulation of disease genes involved in the development of depression and PTSD symptoms after trauma exposure. We obtained a final list of 11 driver causal genes related to MDD symptoms, 13 genes for PTSD symptoms, and 22 genes in PTSD and/or MDD. We observed that these individual or combined disorders shared ESR1, RUNX1, PPARA, and WWOX as driver causal genes, while other genes appeared to be causal driver in the PTSD only or MDD only cases. A number of these identified causal pathways have been previously implicated in the biology or genetics of PTSD and MDD, as well as in preclinical models of amygdala function and fear regulation. Our work provides a promising set of initial pathways that may underlie causal mechanisms in the development of PTSD or MDD in the aftermath of trauma.

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Fig. 1: Determination of dysregulated genes in PTSD.
Fig. 2: Determination of sets of causal genes.
Fig. 3: Determination of causal driver genes.

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Funding

This work was supported by the National Institute on Aging (AG063688), the Howard Hughes Medical Institute, the National Institute for Health (R01 MH094757, KJR; R01 MH094759, CBN), the National Institute of Child Health and Human Development (K12 HD085850, VM), and the Brain and Behavior Research Foundation (BOR). Additional support was provided by the National Center for Advancing Translational Sciences of the NIH under award UL1TR002378.

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Author notes

  1. These authors contributed equally: Stefan Wuchty, Amanda J. Myers

Authors and Affiliations

  1. Department of Computer Science, University of Miami, Coral Gables, FL, USA

    Stefan Wuchty

  2. Department of Biology, University of Miami, Coral Gables, FL, USA

    Stefan Wuchty

  3. Institute of Data Science and Computing, University of Miami, Coral Gables, FL, USA

    Stefan Wuchty

  4. Sylvester Comprehensive Cancer Center, University of Miami, Coral Gables, FL, USA

    Stefan Wuchty

  5. Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL, USA

    Amanda J. Myers, Manuel Ramirez-Restrepo, Felicia Gould & Philip. D. Harvey

  6. Interdepartmental Program in Neuroscience, University of Miami Miller School of Medicine, Miami, FL, USA

    Amanda J. Myers

  7. Interdepartmental Program in Human Genetics and Genomics, University of Miami Miller School of Medicine, Miami, FL, USA

    Amanda J. Myers

  8. Center on Aging, University of Miami Miller School of Medicine, Miami, FL, USA

    Amanda J. Myers

  9. Neurogenomics Division, The Translational Genomics Research Institute, Phoenix, AZ, USA

    Matthew Huentelman & Ryan Richolt

  10. Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA

    Vasiliki Michopolous, Jennifer S. Steven, Aliza P. Wingo, Adriana Lori, Jessica L. Maples-Keller, Alex O. Rothbaum, Barbara O. Rothbaum & Kerry J. Ressler

  11. Department of Psychological Sciences, Case Western Reserve University, Cleveland, OH, USA

    Alex O. Rothbaum

  12. Department of Psychiatry and Behavioral Sciences, Wayne State University, Detroit, MI, USA

    Tanja Jovanovic

  13. McLean Hospital, Harvard Medical School, Belmont, MA, USA

    Kerry J. Ressler

  14. Department of Psychiatry, Dell School of Medicine, Univerity of Texas, Austin, TX, USA

    Charles B. Nemeroff

  15. Institute for Early Life Adversity Research, Dell School of Medicine, Univerity of Texas, Austin, TX, USA

    Charles B. Nemeroff

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  1. Stefan Wuchty
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Corresponding author

Correspondence to Charles B. Nemeroff.

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Conflict of interest

KJR provides fee-for-service consultation for Johnson & Johnson, Verily, and Alkermes. He has received sponsored research unrelated to this work from Brainsway and Takeda. He also holds patents for a number of targets related to improving extinction of fear; however, he has received no equity or income within the last 3 years related to these. He receives or has received research funding from NIMH, NIAAA, HHMI, NARSAD, and the Burroughs Wellcome Foundation.

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Wuchty, S., Myers, A.J., Ramirez-Restrepo, M. et al. Integration of peripheral transcriptomics, genomics, and interactomics following trauma identifies causal genes for symptoms of post-traumatic stress and major depression. Mol Psychiatry 26, 3077–3092 (2021). https://doi.org/10.1038/s41380-021-01084-3

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  • DOI: https://doi.org/10.1038/s41380-021-01084-3

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