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Altered gene expression and PTSD symptom dimensions in World Trade Center responders

Molecular Psychiatry volumeĀ 27,Ā pages 2225ā€“2246 (2022)Cite this article

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Abstract

Despite experiencing a significant trauma, only a subset of World Trade Center (WTC) rescue and recovery workers developed posttraumatic stress disorder (PTSD). Identification of biomarkers is critical to the development of targeted interventions for treating disaster responders and potentially preventing the development of PTSD in this population. Analysis of gene expression from these individuals can help in identifying biomarkers of PTSD. We established a well-phenotyped sample of 371 WTC responders, recruited from a longitudinal WTC responder cohort using stratified random sampling, by obtaining blood, self-reported and clinical interview data. Using bulk RNA-sequencing from whole blood, we examined the association between gene expression and WTC-related PTSD symptom severity on (i) highest lifetime Clinician-Administered PTSD Scale (CAPS) score, (ii) past-month CAPS score, and (iii) PTSD symptom dimensions using a 5-factor model of re-experiencing, avoidance, emotional numbing, dysphoric arousal and anxious arousal symptoms. We corrected for sex, age, genotype-derived principal components and surrogate variables. Finally, we performed a meta-analysis with existing PTSD studies (total Nā€‰=ā€‰1016), using case/control status as the predictor and correcting for these variables. We identified 66 genes significantly associated with total highest lifetime CAPS score (FDR-corrected pā€‰<ā€‰0.05), and 31 genes associated with total past-month CAPS score. Our more granular analyses of PTSD symptom dimensions identified additional genes that did not reach statistical significance in our analyses with total CAPS scores. In particular, we identified 82 genes significantly associated with lifetime anxious arousal symptoms. Several genes significantly associated with multiple PTSD symptom dimensions and total lifetime CAPS score (SERPINA1, RPS6KA1, and STAT3) have been previously associated with PTSD. Geneset enrichment of these findings has identified pathways significant in metabolism, immune signaling, other psychiatric disorders, neurological signaling, and cellular structure. Our meta-analysis revealed 10 genes that reached genome-wide significance, all of which were downregulated in cases compared to controls (CIRBP, TMSB10, FCGRT, CLIC1, RPS6KB2, HNRNPUL1, ALDOA, NACA, ZNF429 and COPE). Additionally, cellular deconvolution highlighted an enrichment in CD4 T cells and eosinophils in responders with PTSD compared to controls. The distinction in significant genes between total lifetime CAPS score and the anxious arousal symptom dimension of PTSD highlights a potential biological difference in the mechanism underlying the heterogeneity of the PTSD phenotype. Future studies should be clear about methods used to analyze PTSD status, as phenotypes based on PTSD symptom dimensions may yield different gene sets than combined CAPS score analysis. Potential biomarkers implicated from our meta-analysis may help improve therapeutic target development for PTSD.

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Fig. 1: Distribution of lifetime and past-month severity scores for Clinician-Administered PTSD Scale (CAPS) and PTSD-symptom dimensions.
Fig. 2: Differential gene expression analysis ofĀ lifetime Clinician-Administered PTSD Scale (CAPS), CAPS past-month, anxious arousal lifetime and anxious arousal past-month in Nā€‰=ā€‰355 World Trade Center first-responders.
Fig. 3: Dust cloud severity and disease comorbidity of Clinician-Administered PTSD Scale (CAPS)Ā lifetime and past-month genome-wide correlations.
Fig. 4: Heatmap of differentially expressed (pā€‰<ā€‰0.05) genes from a gene expression analysis across past-month Clinician-Administered PTSD Scale (CAPS) and symptom dimensions and lifetime CAPS and symptom dimensions in Nā€‰=ā€‰355 World Trade Center first-responders.
Fig. 5: KEGG pathway enrichment of differentially expressed genes in Nā€‰=ā€‰355 World Trade Center first-responders in past-month and lifetime Clinician-Administered PTSD Scale (CAPS).
Fig. 6: Forestplots and volcano plot of genome-wide significant genes from our meta-analysis.
Fig. 7: Cellular deconvolution of immune cells in peripheral blood;Ā significant cell type differences for Clinician-Administered PTSD Scale (CAPS) lifetime and past-month compared to controls are noted.

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The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Author notes

  1. These authors contributed equally: Laura M. Huckins, Adriana Feder.

Authors and Affiliations

  1. Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Shelby Marchese,Ā Jessica S. Johnson,Ā Panos RoussosĀ &Ā Laura M. Huckins

  2. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Leo Cancelmo,Ā Olivia Diab,Ā Leah Cahn,Ā Cindy Aaronson,Ā Nikolaos P. Daskalakis,Ā Jamie Schaffer,Ā Sarah R. Horn,Ā Frank Desarnaud,Ā Linda M. Bierer,Ā Iouri Makotkine,Ā Janine D. Flory,Ā Panos Roussos,Ā Dennis S. Charney,Ā Rachel Yehuda,Ā Laura M. HuckinsĀ &Ā Adriana Feder

  3. Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA, USA

    Nikolaos P. Daskalakis

  4. Department of Family and Social Medicine, Albert Einstein College of Medicine, Bronx, NY, USA

    Clyde Schechter

  5. Department of Psychiatry, James J. Peters Veterans Affairs Medical Center, Bronx, NY, USA

    Frank Desarnaud,Ā Linda M. Bierer,Ā Iouri Makotkine,Ā Janine D. FloryĀ &Ā Rachel Yehuda

  6. Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Michael Crane

  7. Department of Occupational Medicine, Epidemiology and Prevention, Zucker School of Medicine at Hofstra/Northwell, Great Neck, NY, USA

    Jacqueline M. Moline

  8. Environmental and Occupational Health Sciences Institute, School of Public Health, Rutgers University, Piscataway, NJ, USA

    Iris G. Udasin

  9. Department of Medicine, Division of Pulmonary Critical Care and Sleep Medicine, NYU School of Medicine, New York, NY, USA

    Denise J. Harrison

  10. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Panos RoussosĀ &Ā Laura M. Huckins

  11. Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Panos RoussosĀ &Ā Laura M. Huckins

  12. Mental Illness Research, Education and Clinical Centers, James J. Peters Department of Veterans Affairs Medical Center, Bronx, NY, 14068, USA

    Panos RoussosĀ &Ā Laura M. Huckins

  13. Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Dennis S. Charney

  14. Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Dennis S. Charney

  15. Massachusetts General Hospital, Psychiatric and Neurodevelopmental Genetics Unit (PNGU), Boston, MA, USA

    Karestan C. Koenen

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

    Karestan C. Koenen

  17. Harvard School of Public Health, Department of Epidemiology, Boston, MA, USA

    Karestan C. Koenen

  18. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

    Steven M. SouthwickĀ &Ā Robert H. Pietrzak

  19. Department of Veterans Affairs National Center for Posttraumatic Stress Disorder, VA Connecticut Healthcare System, West Haven, CT, USA

    Steven M. SouthwickĀ &Ā Robert H. Pietrzak

  20. Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Laura M. Huckins

Authors
  1. Shelby Marchese
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  2. Leo Cancelmo
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  3. Olivia Diab
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  4. Leah Cahn
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  5. Cindy Aaronson
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  6. Nikolaos P. Daskalakis
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  7. Jamie Schaffer
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  8. Sarah R. Horn
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  9. Jessica S. Johnson
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  10. Clyde Schechter
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  11. Frank Desarnaud
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  12. Linda M. Bierer
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  13. Iouri Makotkine
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  14. Janine D. Flory
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  15. Michael Crane
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  16. Jacqueline M. Moline
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  17. Iris G. Udasin
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  18. Denise J. Harrison
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  19. Panos Roussos
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  20. Dennis S. Charney
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  21. Karestan C. Koenen
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  22. Steven M. Southwick
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  23. Rachel Yehuda
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  24. Robert H. Pietrzak
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  25. Laura M. Huckins
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  26. Adriana Feder
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Contributions

AF, RHP, SMS, RY, NPD, KK, LMB, SM, and LMH designed the present study and provided conceptual input. MC, JMM, IGU, and DJH led collection of data during participantsā€™ first health-monitoring visit to the WTC Health Program, which were incorporated into analyses for the present study. AF, RHP, LC, OD, LC, CA, JS, SRH, RY, FD, IM, LMB, CS, JSJ, and JDF conducted the study. SM, LMH, RHP, and PR conducted the data analyses. SM, LMH, AF, and RHP wrote the paper. RY, SMS, CS, CA and DSC provided input on the manuscript draft. This study was funded by CDC/NIOSH U01 OH010986 (MPIs AF and RHP) and CDC/NIOSH U01 OH010407 (MPIs AF, RHP, and SMS).

Corresponding authors

Correspondence to Laura M. Huckins or Adriana Feder.

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Competing interests

AF and DSC are named co-inventors on a patent application in the US, and several issued patents outside the US, filed by the Icahn School of Medicine at Mount Sinai (ISMMS) related to the use of ketamine for the treatment of PTSD. This intellectual property has not been licensed. DSC is named co-inventor on patents filed by the ISMMS relating to the treatment for treatment-resistant depression, suicidal ideation and other disorders. ISMMS has entered into a licensing agreement with Janssen Pharmaceuticals, Inc. and it has and will receive payments from Janssen under the license agreement related to these patents for the treatment of treatment-resistant depression and suicidal ideation. Consistent with the ISMMS Faculty Handbook (the medical school policy), DSC is entitled to a portion of the payments received by the ISMMS. Since SPRAVATO has received regulatory approval for treatment-resistant depression, ISMMS and thus, through the ISMMS, DSC will be entitled to additional payments, beyond those already received, under the license agreement. DSC is a named co-inventor on several patents filed by ISMMS for a cognitive training intervention to treat depression and related psychiatric disorders. The ISMMS has entered into a licensing agreement with Click Therapeutics, Inc. and has and will receive payments related to the use of this cognitive training intervention for the treatment of psychiatric disorders. In accordance with the ISMMS Faculty Handbook, DSC has received a portion of these payments and is entitled to a portion of any additional payments that the medical school might receive from this license with Click Therapeutics. DSC is a named co-inventor on a patent application filed by the ISMMS for the use of intranasally administered Neuropeptide Y (NPY) for the treatment of mood and anxiety disorders. This intellectual property has not been licensed. The other authors declare no conflicts of interest.

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Marchese, S., Cancelmo, L., Diab, O. et al. Altered gene expression and PTSD symptom dimensions in World Trade Center responders. Mol Psychiatry 27, 2225ā€“2246 (2022). https://doi.org/10.1038/s41380-022-01457-2

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  • DOI: https://doi.org/10.1038/s41380-022-01457-2

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