Transcriptomic organization of the human brain in post-traumatic stress disorder.
Adult
Autopsy
Brain Chemistry
/ genetics
Cohort Studies
Depressive Disorder, Major
/ genetics
Female
Gene Expression Regulation
/ genetics
Gene Regulatory Networks
Genetic Predisposition to Disease
/ genetics
Genome-Wide Association Study
Humans
Interneurons
/ metabolism
Male
Middle Aged
Nerve Tissue Proteins
/ genetics
Sex Characteristics
Stress Disorders, Post-Traumatic
/ genetics
Transcriptome
Young Adult
Journal
Nature neuroscience
ISSN: 1546-1726
Titre abrégé: Nat Neurosci
Pays: United States
ID NLM: 9809671
Informations de publication
Date de publication:
01 2021
01 2021
Historique:
received:
26
03
2020
accepted:
26
10
2020
pubmed:
23
12
2020
medline:
9
3
2021
entrez:
22
12
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33349712
doi: 10.1038/s41593-020-00748-7
pii: 10.1038/s41593-020-00748-7
doi:
Substances chimiques
Elfn1 protein, human
0
Nerve Tissue Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
24-33Investigateurs
Victor E Alvarez
(VE)
David Benedek
(D)
Christopher Brady
(C)
David A Davis
(DA)
Paul E Holtzheimer
(PE)
Terence M Keane
(TM)
Neil Kowell
(N)
Mark W Logue
(MW)
Ann McKee
(A)
Brian Marx
(B)
Deborah Mash
(D)
Mark W Miller
(MW)
William K Scott
(WK)
Thor Stein
(T)
Robert Ursano
(R)
Erika J Wolf
(EJ)
Références
Mota, N. et al. Late-life exacerbation of PTSD symptoms in US veterans: results from the National Health and Resilience in Veterans Study. J. Clin. Psychiatry 77, 348–354 (2016).
pubmed: 27046308
McLaughlin, K. A. et al. Subthreshold posttraumatic stress disorder in the World Health Organization world mental health surveys. Biol. Psychiatry 77, 375–384 (2015).
pubmed: 24842116
Jovanovic, T. et al. Impaired fear inhibition is a biomarker of PTSD but not depression. Depress. Anxiety 27, 244–251 (2010).
pubmed: 20143428
pmcid: 2841213
Yehuda, R. & LeDoux, J. Response variation following trauma: a translational neuroscience approach to understanding PTSD. Neuron 56, 19–32 (2007).
pubmed: 17920012
Koenen, K. C. et al. A high risk twin study of combat-related PTSD comorbidity. Twin Res. 6, 218–226 (2003).
pubmed: 12855071
Koenen, K. C. et al. A twin registry study of the relationship between posttraumatic stress disorder and nicotine dependence in men. Arch. Gen. Psychiatry 62, 1258–1265 (2005).
pubmed: 16275813
Gelernter, J. et al. Genome-wide association study of post-traumatic stress disorder reexperiencing symptoms in >165,000 US veterans. Nat. Neurosci. 22, 1394–1401 (2019).
pubmed: 31358989
pmcid: 6953633
Nievergelt, C. M. et al. International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci. Nat. Commun. 10, 4558 (2019).
pubmed: 31594949
pmcid: 6783435
Stein, M. B. et al. Genomic characterization of posttraumatic stress disorder in a large US military veteran sample. Preprint at bioRxiv https://doi.org/10.1101/764001 (2019).
Kessler, R. C. et al. The global burden of mental disorders: an update from the WHO World Mental Health (WMH) surveys. Epidemiol. Psichiat Soc. 18, 23–33 (2009).
Holbrook, T. L., Hoyt, D. B., Stein, M. B. & Sieber, W. J. Gender differences in long-term posttraumatic stress disorder outcomes after major trauma: women are at higher risk of adverse outcomes than men. J. Trauma 53, 882–888 (2002).
pubmed: 12435938
Baran, S. E., Armstrong, C. E., Niren, D. C. & Conrad, C. D. Prefrontal cortex lesions and sex differences in fear extinction and perseveration. Learn. Mem. 17, 267–278 (2010).
pubmed: 20445082
pmcid: 2862409
Goldstein, J. M., Jerram, M., Abbs, B., Whitfield-Gabrieli, S. & Makris, N. Sex differences in stress response circuitry activation dependent on female hormonal cycle. J. Neurosci. 30, 431–438 (2010).
pubmed: 20071507
pmcid: 2827936
Labonté, B. et al. Sex-specific transcriptional signatures in human depression. Nat. Med. 23, 1102–1111 (2017).
pubmed: 28825715
pmcid: 5734943
Nees, F., Witt, S. H. & Flor, H. Neurogenetic approaches to stress and fear in humans as pathophysiological mechanisms for posttraumatic stress disorder. Biol. Psychiatry 83, 810–820 (2018).
pubmed: 29454655
Young, K. A., Thompson, P. M., Cruz, D. A., Williamson, D. E. & Selemon, L. D. BA11 FKBP5 expression levels correlate with dendritic spine density in postmortem PTSD and controls. Neurobiol. Stress 2, 67–72 (2015).
pubmed: 26844242
pmcid: 4721476
Meng, L. et al. Trauma-specific grey matter alterations in PTSD. Sci. Rep. 6, 33748 (2016).
pubmed: 27651030
pmcid: 5030628
Bonne, O. et al. Resting regional cerebral perfusion in recent posttraumatic stress disorder. Biol. Psychiatry 54, 1077–1086 (2003).
pubmed: 14625150
Britton, J. C., Phan, K. L., Taylor, S. F., Fig, L. M. & Liberzon, I. Corticolimbic blood flow in posttraumatic stress disorder during script-driven imagery. Biol. Psychiatry 57, 832–840 (2005).
pubmed: 15820703
Jovanovic, T. et al. Reduced neural activation during an inhibition task is associated with impaired fear inhibition in a traumatized civilian sample. Cortex 49, 1884–1891 (2013).
pubmed: 23020899
Averill, L. A. et al. Glutamate dysregulation and glutamatergic therapeutics for PTSD: evidence from human studies. Neurosci. Lett. 649, 147–155 (2017).
pubmed: 27916636
Ardi, Z., Albrecht, A., Richter-Levin, A., Saha, R. & Richter-Levin, G. Behavioral profiling as a translational approach in an animal model of posttraumatic stress disorder. Neurobiol. Dis. 88, 139–147 (2016).
pubmed: 26804028
Sun, X., Song, Z., Si, Y. & Wang, J.-H. microRNA and mRNA profiles in ventral tegmental area relevant to stress-induced depression and resilience. Prog. Neuropsychopharmacol. Biol. Psychiatry 86, 150–165 (2018).
pubmed: 29864451
Geuze, E. et al. Reduced GABA
pubmed: 17667960
Möller, A. T., Bäckström, T., Nyberg, S., Söndergaard, H. P. & Helström, L. Women with PTSD have a changed sensitivity to GABA-A receptor active substances. Psychopharmacology 233, 2025–2033 (2016).
pubmed: 25345735
Rosso, I. M. et al. Insula and anterior cingulate GABA levels in posttraumatic stress disorder: preliminary findings using magnetic resonance spectroscopy. Depress. Anxiety 31, 115–123 (2014).
pubmed: 23861191
Sheth, C. et al. Reduced gamma-amino butyric Acid (GABA) and glutamine in the anterior cingulate cortex (ACC) of veterans exposed to trauma. J. Affect. Disord. 248, 166–174 (2019).
pubmed: 30735853
Vaiva, G. et al. Relationship between posttrauma GABA plasma levels and PTSD at 1-year follow-up. Am. J. Psychiatry 163, 1446–1448 (2006).
pubmed: 16877663
Passos, I. C. et al. Inflammatory markers in post-traumatic stress disorder: a systematic review, meta-analysis, and meta-regression. Lancet Psychiatry 2, 1002–1012 (2015).
Kroes, M. C. W., Rugg, M. D., Whalley, M. G. & Brewin, C. R. Structural brain abnormalities common to posttraumatic stress disorder and depression. J. Psychiatry Neurosci. 36, 256–265 (2011).
pubmed: 21418787
pmcid: 3120894
Powers, A. et al. Neural correlates and structural markers of emotion dysregulation in traumatized civilians. Soc. Cogn. Affect. Neursci. 12, 823–831 (2017).
Philip, N. S. et al. Network mechanisms of clinical response to transcranial magnetic stimulation in posttraumatic stress disorder and major depressive disorder. Biol. Psychiatry 83, 263–272 (2018).
pubmed: 28886760
Duncan, L. E. et al. Largest GWAS of PTSD (N=20 070) yields genetic overlap with schizophrenia and sex differences in heritability. Mol. Psychiatry 23, 666–673 (2017).
pubmed: 28439101
pmcid: 5696105
Gandal, M. J. et al. Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap. Science 359, 693–697 (2018).
pubmed: 29439242
pmcid: 5898828
Dunn, H. A., Patil, D. N., Cao, Y., Orlandi, C. & Martemyanov, K. A. Synaptic adhesion protein ELFN1 is a selective allosteric modulator of group III metabotropic glutamate receptors in trans. Proc. Natl Acad. Sci. USA 115, 5022–5027 (2018).
pubmed: 29686062
Stachniak, T. J., Sylwestrak, E. L., Scheiffele, P., Hall, B. J. & Ghosh, A. Elfn1-induced constitutive activation of mGluR7 determines frequency-dependent recruitment of somatostatin interneurons. J. Neurosci. 39, 4461–4474 (2019).
pubmed: 30940718
pmcid: 6554623
Sun, A. X. et al. Direct induction and functional maturation of forebrain GABAergic neurons from human pluripotent stem cells. Cell Rep. 16, 1942–1953 (2016).
pubmed: 27498872
Gusev, A. et al. Integrative approaches for large-scale transcriptome-wide association studies. Nat. Genet. 48, 245–252 (2016).
pubmed: 4767558
pmcid: 4767558
GTEx Consortium The genotype–tissue expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science 348, 648–660 (2015).
pmcid: 4547484
Rytwinski, N. K., Scur, M. D., Feeny, N. C. & Youngstrom, E. A. The co-occurrence of major depressive disorder among individuals with posttraumatic stress disorder: a meta analysis. J. Trauma. Stress 26, 299–309 (2013).
pubmed: 23696449
Seney, M. L. et al. Opposite molecular signatures of depression in men and women. Biol. Psychiatry 84, 18–27 (2018).
pubmed: 29548746
pmcid: 6014892
Seney, M. L., Tripp, A., McCune, S., Lewis, D. A. & Sibille, E. Laminar and cellular analyses of reduced somatostatin gene expression in the subgenual anterior cingulate cortex in major depression. Neurobiol. Dis. 73, 213–219 (2015).
pubmed: 25315685
Lewis, D. A. & Sweet, R. A. Schizophrenia from a neural circuitry perspective: advancing toward rational pharmacological therapies. J. Clin. Invest. 119, 706–716 (2009).
pubmed: 19339762
pmcid: 2662560
Peters, J., Dieppa-Perea, L. M., Melendez, L. M. & Quirk, G. J. Induction of fear extinction with hippocampal–infralimbic BDNF. Science 328, 1288–1290 (2010).
pubmed: 20522777
pmcid: 3570764
Etkin, A. & Wager, T. D. Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am. J. Psychiatry 164, 1476–1488 (2007).
pubmed: 17898336
pmcid: 3318959
Przanowski, P. et al. The signal transducers Stat1 and Stat3 and their novel target Jmjd3 drive the expression of inflammatory genes in microglia. J. Mol. Med. 92, 239–254 (2013).
pubmed: 24097101
pmcid: 3940857
Licznerski, P. et al. Decreased SGK1 expression and function contributes to behavioral deficits induced by traumatic stress. PLoS Biol. 13, e1002282 (2015).
pubmed: 26506154
pmcid: 4623974
Holmes, S. E. et al. Altered metabotropic glutamate receptor 5 markers in PTSD: in vivo and postmortem evidence. Proc. Natl Acad. Sci. USA 114, 8390–8395 (2017).
pubmed: 28716937
Koenen, K. C. et al. Polymorphisms in FKBP5 are associated with peritraumatic dissociation in medically injured children. Mol. Psychiatry 10, 1058–1059 (2005).
pubmed: 16088328
Labonté, B. et al. Gadd45b mediates depressive-like role through DNA demethylation. Sci. Rep. 9, 4615 (2019).
pubmed: 30874581
pmcid: 6420662
Spitzer, R. L., Williams, J. B. W., Gibbon, M. & First, M. B. The structured clinical interview for DSM-III-R (SCID): I: history, rationale, and description. Arch. Gen. Psychiatry 49, 624–629 (1992).
pubmed: 1637252
Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).
pubmed: 25516281
pmcid: 25516281
Jaffe, A. E. et al. Developmental and genetic regulation of the human cortex transcriptome illuminate schizophrenia pathogenesis. Nat. Neurosci. 21, 1117–1125 (2018).
pubmed: 30050107
pmcid: 6438700
Feng, Y.-Y. et al. RegTools: integrated analysis of genomic and transcriptomic data for discovery of splicing variants in cancer. Preprint at bioRxiv https://doi.org/10.1101/436634 (2020).
Kim, D. et al. TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol. 14, R36 (2013).
pubmed: 4053844
pmcid: 4053844
Raudvere, U. et al. g:Profiler: a web server for functional enrichment analysis and conversions of gene lists (2019 update). Nucleic Acids Res. 47, W191–W198 (2019).
pubmed: 31066453
pmcid: 6602461
Langfelder, P. & Horvath, S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics 9, 559 (2008).
pubmed: 19114008
pmcid: 2631488
Zhang, B. & Horvath, S. A general framework for weighted gene co-expression network analysis. Stat. Appl. Genet. Mol. Biol. 4, Article17 (2005).
pubmed: 16646834
Dougherty, J. D., Schmidt, E. F., Nakajima, M. & Heintz, N. Analytical approaches to RNA profiling data for the identification of genes enriched in specific cells. Nucleic Acids Res. 38, 4218–4230 (2010).
pubmed: 20308160
pmcid: 2910036
Xu, X., Wells, A. B., O’Brien, D. R., Nehorai, A. & Dougherty, J. D. Cell type-specific expression analysis to identify putative cellular mechanisms for neurogenetic disorders. J. Neurosci. 34, 1420–1431 (2014).
pubmed: 24453331
pmcid: 3898298
Zhang, Y. et al. Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse. Neuron 89, 37–53 (2016).
pubmed: 26687838
Margolin, A. A. et al. ARACNE: an algorithm for the reconstruction of gene regulatory networks in a mammalian cellular context. BMC Bioinformatics 7 Suppl. 1, S7 (2006).
pubmed: 16723010
Hu, Y. et al. A statistical framework for cross-tissue transcriptome-wide association analysis. Nat. Genet. 51, 568–576 (2019).
pubmed: 30804563
pmcid: 6788740
Newman, A. M. et al. Determining cell type abundance and expression from bulk tissues with digital cytometry. Nat. Biotechnol. 37, 773–782 (2019).
pubmed: 31061481
pmcid: 6610714
Zhu, Y. et al. Spatiotemporal transcriptomic divergence across human and macaque brain development. Science 362, eaat8077 (2018).
pubmed: 30545855
pmcid: 6900982