Cited by 80Posttraumatic Stress Disorder ResearchGenetic Associations and EpidemiologyChild Abuse and Trauma

A genome-wide identified risk variant for PTSD is a methylation quantitative trait locus and confers decreased cortical activation to fearful faces

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Almli, Lynn M., Stevens, Jennifer S., Smith, Alicia K., Kilaru, Varun, Meng, Qian, Flory, Janine, Abu‐Amara, Duna, Hammamieh, Rasha +9 more·2015·American Journal of Medical Genetics Part B: Neuropsychiatric Genetics

Abstract

Genetic factors appear to be highly relevant to predicting differential risk for the development of post‐traumatic stress disorder (PTSD). In a discovery sample, we conducted a genome‐wide association study (GWAS) for PTSD using a small military cohort (Systems Biology PTSD Biomarkers Consortium; SBPBC, N = 147) that was designed as a case‐controlled sample of highly exposed, recently returning veterans with and without combat‐related PTSD. A genome‐wide significant single nucleotide polymorphism (SNP), rs717947, at chromosome 4p15 (N = 147, β = 31.34, P = 1.28 × 10 −8 ) was found to associate with the gold‐standard diagnostic measure for PTSD (the Clinician Administered PTSD Scale). We conducted replication and follow‐up studies in an external sample, a larger urban community cohort (Grady Trauma Project, GTP, N = 2006), to determine the robustness and putative functionality of this risk variant. In the GTP replication sample, SNP rs717947 associated with PTSD diagnosis in females (N = 2006, P = 0.005), but not males. SNP rs717947 was also found to be a methylation quantitative trait locus (meQTL) in the GTP replication sample (N = 157, P = 0.002). Further, the risk allele of rs717947 was associated with decreased medial and dorsolateral cortical activation to fearful faces (N = 53, P < 0.05) in the GTP replication sample. These data identify a genome‐wide significant polymorphism conferring risk for PTSD, which was associated with differential epigenetic regulation and with differential cortical responses to fear in a replication sample. These results may provide new insight into understanding genetic and epigenetic regulation of PTSD and intermediate phenotypes that contribute to this disorder. © 2015 Wiley Periodicals, Inc.

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  • There is accumulating evidence for gene programming and epigenetic regulation of specific genes in the pathophysiology of PTSD in humans.

    “There is accumulating evidence for gene programming and epigenetic regulation of specific genes in the pathophysiology of PTSD in humans (399–402).”

    From Developmental Trajectories of Early Life Stress and Trauma: A Narrative Review on Neurobiological Aspects Beyond Stress System Dysregulation (2019) · cites this paper as [402]

    The Results section (‘rs717947 is a Methylation QTL’; page unavailable) links a PTSD-associated variant to differences in DNA methylation in a human cohort. But the Discussion (page unavailable) says the region is intergenic and its effects on neighboring genes remain uncertain; the paper does not establish programming or epigenetic regulation of specific genes in PTSD pathophysiology. (LLM, conf=0.85)

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Authors
Almli, L. M., Stevens, J. S., Smith, A. K., Kilaru, V., Meng, Q., Flory, J., Abu‐Amara, D., Hammamieh, R., Yang, R., Mercer, K. B., Binder, E. B., Bradley, B., Hamilton, S., Jett, M., Yehuda, R., Marmar, C. R., & Ressler, K. J.
Affiliations
  • Emory University (US)
  • Department of Psychiatry University Medical Center New York New York
  • James J. Peters VA Medical Center (US)
  • Department of Psychiatry New York University Steven and Alexandra Cohen Veterans Center for Posttraumatic Stress and Traumatic Brain Injury New York New York
  • United States Army (US)
  • Frederick National Laboratory for Cancer Research (US)
  • United States Department of Veterans Affairs (US)
  • University of California, San Francisco (US)
  • New York University (US)
  • Howard Hughes Medical Institute (US)
Corresponding author
Ressler, Kerry J.
Venue
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics
Publisher
Wiley
Published
2015-05-18
Volume
168
Issue
5
Pages
327-336
ISSN
  • 1552-4841 (ISSN-L)
  • 1552-485X
OpenAlex
W1905797464
Cited by
80
References
44
Citations by year
2026: 1 · 2025: 4 · 2024: 5 · 2023: 2 · 2022: 6 · 2021: 3 · 2020: 4 · 2019: 12 · 2018: 13 · 2017: 12 · 2016: 12 · 2015: 6
FWCI
17.80
Type
journal article
Language
en
Open access
Locations
  • American Journal of Medical Genetics Part B Neuropsychiatric Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • MPG.PuRe (Max Planck Society) (submittedVersion)
Funders
  • National Institutes of Health (MH87977, MH096764)
  • U.S. Department of Defense (W81XWH-09-2-0044, W911NF-09-1-0298)
Topics
  • Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Social Sciences › Psychology › Clinical Psychology › Child Abuse and Trauma
Keywords
post-traumatic stress disorder, DNA methylation, epigenetic regulation, cortical activation, fearful faces, sex differences, combat-related PTSD, veterans, genome-wide association study
MeSH terms
Adult, Face, Facial Expression, Fear, Female, Humans, Male, Risk Factors, Stress Disorders, Post-Traumatic, Veterans, DNA Methylation, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Epigenesis, Genetic, Genome-Wide Association Study

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