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Genetically regulated multi-omics study for symptom clusters of posttraumatic stress disorder highlights pleiotropy with hematologic and cardio-metabolic traits

Molecular Psychiatry volume 27, pages 1394–1404 (2022)Cite this article

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Abstract

Posttraumatic stress disorder (PTSD) is a psychiatric disorder that may arise in response to severe traumatic event and is diagnosed based on three main symptom clusters (reexperiencing, avoidance, and hyperarousal) per the Diagnostic Manual of Mental Disorders (version DSM-IV-TR). In this study, we characterized the biological heterogeneity of PTSD symptom clusters by performing a multi-omics investigation integrating genetically regulated gene, splicing, and protein expression in dorsolateral prefrontal cortex tissue within a sample of US veterans enrolled in the Million Veteran Program (N total = 186,689). We identified 30 genes in 19 regions across the three PTSD symptom clusters. We found nine genes to have cell-type specific expression, and over-representation of miRNA-families – miR-148, 30, and 8. Gene-drug target prioritization approach highlighted cyclooxygenase and acetylcholine compounds. Next, we tested molecular-profile based phenome-wide impact of identified genes with respect to 1678 phenotypes derived from the Electronic Health Records of the Vanderbilt University biorepository (N = 70,439). Lastly, we tested for local genetic correlation across PTSD symptom clusters which highlighted metabolic (e.g., obesity, diabetes, vascular health) and laboratory traits (e.g., neutrophil, eosinophil, tau protein, creatinine kinase). Overall, this study finds comprehensive genomic evidence including clinical and regulatory profiles between PTSD, hematologic and cardiometabolic traits, that support comorbidities observed in epidemiologic studies of PTSD.

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Fig. 1: Study overview and identified genes.
Fig. 2: Tissue and miRNA network.
Fig. 3: PheWAS and LabWAS of TWAS-identified genes in BioVU cohort.
Fig. 4: Phenome-wide colocalization of identified genes and over-representated categories.
Fig. 5: Matrix plot of local genetic correlation between three PTSD symptom clusters and colocalizing traits (few presented here on the left y-axis).

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Data availability

All the data is available in Supplementary files. If you need further clarification, please contact the corresponding author. GWAS summary statistics: https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs001672.v6.p1. TWAS method: http://gusevlab.org/projects/fusion/. Splicing and Gene Expression Weights: http://gusevlab.org/projects/fusion/. Proteome weights: https://www.synapse.org/#!Synapse:syn23627957. Open Targets: https://genetics.opentargets.org/. UKBB Summary Statistics: http://www.nealelab.is/uk-biobank. LAVA: https://github.com/josefin-werme/LAVA. CLUE: https://clue.io/.

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Acknowledgements

The authors thank publicly available resources from Neale Lab (UK Biobank GWAS statistics), the Million Veteran Program (GWAS statistics via dbGaP), and Common-Mind Consortium (pretrained dlPFC models). The authors acknowledge support from the National Institutes of Health (R21DC018098, R33DA047527, F32MH122058, U54MD010722-04, R01MH113362, R01MH118223, R56MH120736, T32HG008341) and One Mind. The BioVU projects at Vanderbilt University Medical Center are supported by numerous sources: institutional funding, private agencies, and federal grants. These include the NIH-funded Shared Instrumentation Grant S10OD017985 and S10RR025141; CTSA grants UL1TR002243, UL1TR000445, and UL1RR024975 from the National Center for Advancing Translational Sciences. Its contents are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health. Genomic data are also supported by investigator-led projects that include U01HG004798, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962, R01HD074711; and additional funding sources listed at https://victr.vumc.org/biovu-funding/.

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Authors and Affiliations

  1. Department of Psychiatry, Yale School of Medicine, West Haven, CT, 06516, USA

    Gita A. Pathak, Frank R. Wendt, Cassie Overstreet, Dora Koller, Daniel S. Tylee, Flavio De Angelis, Brenda Cabrera Mendoza, Daniel F. Levey, John H. Krystal, Robert H. Pietrzak, Joel Gelernter & Renato Polimanti

  2. VA CT Healthcare Center, West Haven, CT, 06516, USA

    Gita A. Pathak, Frank R. Wendt, Cassie Overstreet, Dora Koller, Daniel S. Tylee, Flavio De Angelis, Brenda Cabrera Mendoza, Daniel F. Levey, John H. Krystal, Joel Gelernter & Renato Polimanti

  3. Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    Kritika Singh, Tyne W. Fleming, Flavio De Angelis & Lea K. Davis

  4. Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA

    Kritika Singh, Tyne W. Fleming & Lea K. Davis

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

    Karestan C. Koenen

  6. Clinical Neurosciences Division, U.S. Department of Veterans Affairs National Center for PTSD, VA Connecticut Healthcare System, New Haven, CT, USA

    John H. Krystal & Robert H. Pietrzak

  7. Cardiology Section, Department of Medicine, VA Boston Healthcare System, Boston, MA, USA

    Christopher O’ Donell

  8. Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA

    Christopher O’ Donell & J. Michael Gaziano

  9. Department of Medicine, Harvard Medical School, Boston, MA, USA

    Christopher O’ Donell & J. Michael Gaziano

  10. Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA

    J. Michael Gaziano

  11. Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Yale School of Medicine, 15 York Street, LLCI 1004D, Box 208018, New Haven, CT, 06520, USA

    Guido Falcone

  12. VA San Diego Healthcare System, Psychiatry Service, San Diego, CA, USA

    Murray B. Stein

  13. Department of Psychiatry, University of California San Diego, La Jolla, CA, USA

    Murray B. Stein

  14. Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, CA, USA

    Murray B. Stein

  15. Departments of Computational Medicine, Human Genetics, Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA

    Bogdan Pasaniuc

  16. Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Nicholas Mancuso

  17. Center for Genetic Epidemiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Nicholas Mancuso

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  1. Gita A. Pathak
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Contributions

GAP designed the study, analyzed the data, and wrote the manuscript draft. KS, FRW, TWF, and CO analyzed the data and drafted the manuscript. DST provided clinical expertise for phenotype harmonization between cohorts. All the other authors provided critical feedback, context interpretation, draft revision, and editing. LKD and RP supervised the study, reviewed, and edited the manuscript.

Corresponding author

Correspondence to Renato Polimanti.

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Competing interests

RP and JG are paid for their editorial work on the journal Complex Psychiatry. JHK has served as a scientific consultant (Individual Consultant Agreements less than $5000 per year) to Amgen, AstraZeneca Pharmaceuticals, Bigen, Idec, MA, Biomedisyn Corporation, Forum Pharmaceuticals, Janssen Research & Development, Otsuka America Pharmaceutical, Sunovion Pharmaceuticals, Takeda Industries, and Taisho Pharmaceutical Co; is on the Scientific Advisory Board for Biohaven Pharmaceuticals, Blackthorn Therapeutics, Lohocla Research Corporation, Luc Therapeutics, Pfizer Pharmaceuticals, Tand RImaran Pharma; holds stock in Biohaven Pharmaceuticals Medical Sciences and stock options in Blackthorn Therapeutics and Luc Therapeutics; and is editor of Biological Psychiatry (income greater than $10,000 per year). JG is named as an inventor on PCT patent application no. 15/878,640 entitled “Genotype-guided dosing of opioid agonists,” filed January 24, 2018. RHP is a scientific consultant to Cogstate for work that bears no relationship to the current study. The other authors report no biomedical financial interests or potential conflicts of interest.

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Pathak, G.A., Singh, K., Wendt, F.R. et al. Genetically regulated multi-omics study for symptom clusters of posttraumatic stress disorder highlights pleiotropy with hematologic and cardio-metabolic traits. Mol Psychiatry 27, 1394–1404 (2022). https://doi.org/10.1038/s41380-022-01488-9

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