An epigenome-wide DNA methylation study of PTSD and depression in World Trade Center responders
Open accessAbstract
Previous epigenome-wide association studies (EWAS) of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) have been inconsistent. This may be due to small sample sizes, and measurement and tissue differences. The current two EWA analyses of 473 World Trade Center responders are the largest to date for both PTSD and MDD. These analyses investigated DNA methylation patterns and biological pathways influenced by differentially methylated genes associated with each disorder. Methylation was profiled on blood samples using Illumina 450 K Beadchip. Two EWA analyses compared current versus never PTSD, and current versus never MDD, adjusting for cell types and demographic confounders. Pathway and gene set enrichment analyses were performed to understand the complex biological systems of PTSD and MDD. No significant epigenome-wide associations were found for PTSD or MDD at an FDR P<0.05. The majority of genes with differential methylation at a suggestive threshold did not overlap between the two disorders. Pathways significant in PTSD included a regulator of synaptic plasticity, oxytocin signaling, cholinergic synapse and inflammatory disease pathways, while only phosphatidylinositol signaling and cell cycle pathways emerged in MDD. The failure of the current EWA analyses to detect significant epigenome-wide associations is in contrast with disparate findings from previous, smaller EWA and candidate gene studies of PTSD and MDD. Enriched gene sets involved in several biological pathways, including stress response, inflammation and physical health, were identified in PTSD, supporting the view that multiple genes play a role in this complex disorder.
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Two EWAS studies in PTSD found differences in DNAm across genes part of biological pathways involved with inflammation and immune response.
“Two EWAS studies in PTSD found differences in DNAm across genes part of biological pathways involved with inflammation and immune response (Kuan et al., 2017; Uddin et al., 2010).”
From Can epigenetics shine a light on the biological pathways underlying major mental disorders? (2022) · cites this paper as Kuan et al., 2017
The Results (Pathway and gene ontology analyses) identify PTSD-associated pathways, including an inflammatory bowel disease pathway, and the Discussion (Biological pathways) describes several immunity-related pathways. But the Abstract reports no significant epigenome-wide methylation associations, and the Discussion (EWAS findings) says no individual immune-system gene was identified. The claim captures the pathway findings but overstates the evidence for DNA methylation differences in individual genes. (LLM, conf=0.84)
Experimental — accuracy not yet measuredEpigenetic disruption has been implicated in cancer, aging, and a range of complex diseases, including psychiatric disorders such as depression and PTSD.
“Epigenetic disruption has been clearly implicated in cancer, aging, and a range of complex diseases, including psychiatric disorders, such as depression [33] and PTSD [34,35].”
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Braný, D., Dvorská, D., Lockwood, L. E., Strnádel, J., & Youssef, N. A. (2022) · Elsevier eBooks · doi:10.1016/b978-0-12-823039-8.00011-3
Sociobehavioral-induced epigenetic variation and psychiatric diseases
Petroff, R., Goodrich, J. M., Bakulski, K. M., & Dolinoy, D. C. (2023) · Elsevier eBooks · doi:10.1016/b978-0-12-824010-6.00032-0
Hoffarth, B., Reuter, E., & Richter, S. (2022) · Campus Verlag eBooks · doi:10.12907/978-3-593-44545-8
Logue, M. W., Miller, M. W., Wolf, E. J., Huber, B. R., Morrison, F. G., Zhou, Z., Zheng, Y., Smith, A. K., Daskalakis, N. P., Ratanatharathorn, A. D., et al. (2020) · Figshare · doi:10.6084/m9.figshare.11986023
Sumner, J. A., Gambazza, S., Gao, X., Baccarelli, A., Uddin, M., & McLaughlin, K. A. (2022) · Figshare · doi:10.6084/m9.figshare.19556175
Grillakis, C. E., Madden, S. V., Brick, L. A. D., & Merrill, S. M. (2026) · Frontiers in Psychology · doi:10.3389/fpsyg.2026.1875411
- Authors
- Kuan, P.-F., Waszczuk, M. A., Kotov, R., Marsit, C. J., Guffanti, G., Gonzalez, A., Yang, X., Koenen, K., Bromet, E., & Luft, B. J.
- Affiliations
- Stony Brook University (US)
- Emory University (US)
- Harvard University (US)
- Corresponding author
- Luft, B J
- Venue
- Translational Psychiatry
- Published
- 2017-06-27
- Volume
- 7
- Issue
- 6
- Pages
- e1158-e1158
- ISSN
- 2158-3188 (ISSN-L)
- PMC
- PMC5537648
- OpenAlex
- W2634894186
- Cited by
- 103
- References
- 80
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 10 · 2023: 8 · 2022: 17 · 2021: 16 · 2020: 15 · 2019: 12 · 2018: 13 · 2017: 1
- FWCI
- 13.91
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Translational Psychiatry (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Stony Brook University
- Centers for Disease Control and Prevention
- National Institute for Occupational Safety and Health (U01OH010416, U01 OH010416-01)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- post-traumatic stress disorder, major depressive disorder, DNA methylation, epigenome-wide association study, World Trade Center responders, differentially methylated genes, gene set enrichment analysis, synaptic plasticity, oxytocin signaling, cholinergic synapses, phosphoinositide signaling, cell cycle, stress response, inflammation
- MeSH terms
- Major Depressive Disorder, Depressive Disorder, Major, Humans, Male, Middle Aged, Stress Disorders, Post-Traumatic, Signal Transduction, CpG Islands, DNA Methylation, Epigenesis, Genetic, September 11 Terrorist Attacks, Genome-Wide Association Study, Epigenomics, Emergency Responders
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