Transcriptomic organization of the human brain in post-traumatic stress disorder

Abstract

Despite extensive study of the neurobiological correlates of post-traumatic stress disorder (PTSD), little is known about its molecular determinants. Here, differential gene expression and network analyses of four prefrontal cortex subregions from postmortem tissue of people with PTSD demonstrate extensive remodeling of the transcriptomic landscape. A highly connected downregulated set of interneuron transcripts is present in the most significant gene network associated with PTSD. Integration of this dataset with genotype data from the largest PTSD genome-wide association study identified the interneuron synaptic gene ELFN1 as conferring significant genetic liability for PTSD. We also identified marked transcriptomic sexual dimorphism that could contribute to higher rates of PTSD in women. Comparison with a matched major depressive disorder cohort revealed significant divergence between the molecular profiles of individuals with PTSD and major depressive disorder despite their high comorbidity. Our analysis provides convergent systems-level evidence of genomic networks within the prefrontal cortex that contribute to the pathophysiology of PTSD in humans.

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Fig. 1: Comparisons of transcriptomic signatures between PTSD and control PFC subregions.
Fig. 2: Regional gene co-expression analysis of PTSD PFC.
Fig. 3: PTSD TWAS.
Fig. 4: Differential expression profiles reveal sex-specific PTSD transcriptomic signatures across PFC regions.
Fig. 5: Divergent and shared transcriptomic-specific features between PTSD and MDD.

Data availability

Summary statistic data are available in Supplementary Tables 1, 6, 9 and 10. The data that support the findings of this study are available from the corresponding authors upon reasonable request.

Code availability

All codes used in this study are freely available online and can be found at https://github.com/mjgirgenti/PTSDCorticalTranscriptomics.

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Acknowledgements

We thank M. Picciotto, C. Pittenger and A. Che for critically reading the manuscript. We thank R. Terwilliger for technical assistance. We are grateful to the families who donated to this research. This work was supported with resources and use of facilities at the VA Connecticut Health Care System, West Haven, CT, the Central Texas Veterans Health Care System, Temple, TX, the Durham VA Healthcare System, Durham, NC, the VA San Diego Healthcare System, La Jolla, CA, the VA Boston Healthcare System, Boston, MA, USA, and the National Center for PTSD, US Department of Veterans Affairs. The research reported here was supported by the Department of Veterans Affairs, Veteran Health Administration, VISN1 Career Development Award and a Brain and Behavior Research Foundation Young Investigator Award to M.J.G. and by NIMH grants MH093897 and MH105910 to R.S.D. The views expressed here are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs (VA) or the US government.

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M.J.G., M.J.F., J.H.K. and R.S.D. conceived the project, designed the experiments and wrote the manuscript. M.J.G. also generated and analyzed all of the data. J.W., D.J. and H.Z. oversaw all bioinformatics analyses for gene expression, network analysis and TWAS. M.B.S. and J.G. contributed GWAS data. D.A.C., K.A.Y., B.R.H. and D.E.W. contributed to the study design. All authors contributed to the preparation of the manuscript.

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Correspondence to Matthew J. Girgenti or Matthew J. Friedman or John H. Krystal or Hongyu Zhao.

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Competing interests

J.G. is named as a co-inventor on PCT patent application number 15/878,640 entitled “Genotype-guided dosing of opioid agonists”, filed 24 January 2018. M.B.S. has in the past 3 years been a consultant for Aptinyx, Bionomics, EpiVario, Greenwich Biosciences, Janssen, and Jazz Pharmaceuticals. He also receives payment from the following entities for editorial work: Biological Psychiatry (published by Elsevier), Depression and Anxiety (published by Wiley) and UpToDate. J.H.K. has consulting agreements (less than US$10,000 per year) with the following: AstraZeneca Pharmaceuticals, Biogen, Idec, MA, Biomedisyn Corporation, Bionomics, Limited (Australia), Boehringer Ingelheim International, COMPASS Pathways, Limited, United Kingdom, Concert Pharmaceuticals, Inc., Epiodyne, Inc., EpiVario, Inc., Heptares Therapeutics, Limited (UK), Janssen Research & Development, Otsuka America, Pharmaceutical, Inc., Perception Neuroscience Holdings, Inc., Spring Care, Inc., Sunovion Pharmaceuticals, Inc., Takeda Industries and Taisho Pharmaceutical Co., Ltd. J.H.K. serves on the scientific advisory boards of Bioasis Technologies, Inc., Biohaven Pharmaceuticals, BioXcel Therapeutics, Inc. (Clinical Advisory Board), BlackThorn Therapeutics, Inc., Cadent Therapeutics (Clinical Advisory Board), Cerevel Therapeutics, LLC., EpiVario, Inc., Lohocla Research Corporation, PsychoGenics, Inc.; is on the board of directors of Inheris Biopharma, Inc.; has stock options with Biohaven Pharmaceuticals Medical Sciences, BlackThorn Therapeutics, Inc., EpiVario, Inc. and Terran Life Sciences; and is editor of Biological Psychiatry with income greater than $10,000. R.S.D. has received consulting fees from Taisho, Johnson & Johnson and Naurex; and receives grant support from Taisho, Johnson & Johnson, Naurex, Navitor, Allergan, Lundbeck and Lilly. None of the above listed companies or funding agencies had any influence on the content of this article.

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Extended data

Extended Data Fig. 1 Transcriptomic concordance comparisons between PTSD and other neuropsychiatric disorders.

a, PTSD transcriptomic profiles were compared with 5 other neuropsychiatric disorders. Individual cortical regions were compared to meta-analyzed transcriptomic signatures for autism spectrum disorder (ASD), schizophrenia (SCZ), bipolar disorder (BP), major depression disorder (MDD(*)), alcohol abuse disorder (AAD), and control disease irritable bowel syndrome (IBS). There was a significant correlation between PTSD and AAD in the dACC. b, Comparison of psychiatric control cohort MDD transcriptomic signature to the 5 psychiatric disorders. Error bars indicate mean ± s.d. **bootstrap P=0.007, *bootstrap P=0.04, n= 9304 genes. P values were calculated with null distribution from bootstrap and not corrected for multiple comparisons.

Extended Data Fig. 2 Extended WGCNA of PTSD combined-sex modules.

a, Extended circos plot from Fig. 2a, including complete regional break down and cell type enrichment for each module. Each slice of the chart represents a coexpression module. The key for the circos plot is on the left. The outermost rectangle is the arbitrary color name. The outermost concentric circles represent degree to which DEGs are contained within the module for each brain region and the inner concentric circles indicate cell-type enrichment (colors reflect corrected FET P-values with key provided). b, Gene ontology analysis of each module with at least 2 GO terms. Top two significant ontologies are plotted.

Extended Data Fig. 3 Sex-specific PTSD associated modules with enrichment of cell-type markers.

Cell type enrichment was found in 22 modules in the combined-sex comparison (a), 23 female specific modules (b), and 23 male specific modules (c).

Extended Data Fig. 4 RNA-seq cell type deconvolution and population size estimate for all regions in PTSD and MDD.

Individual cell type population proportions for control (salmon), MDD (green), and PTSD (blue) in dlPFC(a), OFC(b), dACC(c), and sgPFC(d). ExN, excitatory neuron; IntN, interneuron; Oligo, oligodendrocyte; Astro, astrocyte; OPC, oligodendrocyte precursor cell; Vsmc, vascular smooth muscle cell; Endo, endothelial cell. Error bars indicate mean ± s.e.m. one-way ANOVA by diagnosis and region. Box border maxima and minima are ± 1.5 s.d., box borders are 25% and 75% of quantile and the center is the median.

Extended Data Fig. 5 Ontological terms associated with sex-specific regional transcriptomic changes.

Top gene ontology (GO) enrichments for all differentially expressed features across female OFC (a), female sgPFC (b) and male dlPFC (c) including cell compartment, molecular function, and biological function ontologies.

Extended Data Fig. 6 Extended WGCNA of PTSD sex-specific modules and gene ontologies.

Extended circos plot from Fig. 4f (a) and g(b), including complete regional break down and cell type enrichment for each module. Each slice of the chart represents a coexpression module. The key for the circos plot is on the left. The outermost rectangle is the arbitrary color name. The outermost concentric circles represent degree to which DEGs are contained within the module for each brain region and the inner concentric circles indicate cell-type enrichment (colors reflect corrected FET P-values with key provided). Gene ontology analysis of each female-specific modules (c) and male-specific modules (d) with at least 2 GO terms. Top two significant ontologies are plotted.

Extended Data Fig. 7 Differential expression profiles in humans with MDD reveal sex-specific transcriptomic profiles across PFC subregions.

a, Volcano plots display differential regulation of genes in PFC of all MDD cases. b, Volcano plots display sex-specific DEGs in females (top) and males (bottom) across PFC subregions. Blue dots indicate down regulation and red dots indicate up regulation compared to control.

Extended Data Fig. 8 Module correlation between PTSD and MDD gene co-expression modules.

The quantile of correlation among 2000 permutations was calculated for each PTSD and MDD module. Blue line indicates modules above the 97.5% quantile that are significantly convergent and the red line indicates the bottom 2.5% quantile that are significantly divergent. In the combined sex comparison(a) there are 16 convergent modules and 12 divergent modules, in females there are 9 convergent and 19 divergent modules(b), and in males there are 15 convergent and 5 divergent modules(c).

Extended Data Fig. 9 Sex- and cell-type specific network convergence of PTSD and MDD.

a, Female and male module association across PTSD (y-axis) and MDD (x-axis). Plots show β values of module eigengene association with disease. Cell type marker enrichment of combined sex (b), female (c) and male (d) modules in combined disease network analysis.

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Supplementary Figs. 1–3, and consortia authors for the Traumatic Stress Group and the MVP.

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Girgenti, M.J., Wang, J., Ji, D. et al. Transcriptomic organization of the human brain in post-traumatic stress disorder. Nat Neurosci 24, 24–33 (2021). https://doi.org/10.1038/s41593-020-00748-7

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