Abstract
Biomarkers that predict symptom trajectories after trauma can facilitate early detection or intervention for posttraumatic stress disorder (PTSD) and may also advance our understanding of its biology. Here, we aimed to identify trajectory-based biomarkers using blood transcriptomes collected in the immediate aftermath of trauma exposure. Participants were recruited from an Emergency Department in the immediate aftermath of trauma exposure and assessed for PTSD symptoms at baseline, 1, 3, 6, and 12 months. Three empirical symptom trajectories (chronic-PTSD, remitting, and resilient) were identified in 377 individuals based on longitudinal symptoms across four data points (1, 3, 6, and 12 months), using latent growth mixture modeling. Blood transcriptomes were examined for association with longitudinal symptom trajectories, followed by expression quantitative trait locus analysis. GRIN3B and AMOTL1 blood mRNA levels were associated with chronic vs. resilient post-trauma symptom trajectories at a transcriptome-wide significant level (N = 153, FDR-corrected p value = 0.0063 and 0.0253, respectively). We identified four genetic variants that regulate mRNA blood expression levels of GRIN3B. Among these, GRIN3B rs10401454 was associated with PTSD in an independent dataset (N = 3521, p = 0.04). Examination of the BrainCloud and GTEx databases revealed that rs10401454 was associated with brain mRNA expression levels of GRIN3B. While further replication and validation studies are needed, our data suggest that GRIN3B, a glutamate ionotropic receptor NMDA type subunit-3B, may be involved in the manifestation of PTSD. In addition, the blood mRNA level of GRIN3B may be a promising early biomarker for the PTSD manifestation and development.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Kar N. Cognitive behavioral therapy for the treatment of post-traumatic stress disorder: a review. Neuropsychiatr Dis Treat. 2011;7:167–81. https://doi.org/10.2147/NDT.S10389.
Shalev AY, Ankri Y, Israeli-Shalev Y, Peleg T, Adessky R, Freedman S. Prevention of posttraumatic stress disorder by early treatment: results from the Jerusalem Trauma Outreach And Prevention study. Arch Gen Psychiatry. 2012;69:166–76. https://doi.org/10.1001/archgenpsychiatry.2011.127.
Rothbaum BO, Kearns MC, Reiser E, Davis JS, Kerley KA, Rothbaum AO, et al. Early intervention following trauma may mitigate genetic risk for PTSD in civilians: a pilot prospective emergency department study. J Clin Psychiatry. 2014;75:1380–7. https://doi.org/10.4088/JCP.13m08715.
Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62:593–602. https://doi.org/10.1001/archpsyc.62.6.593.
Wolf EJ, Miller MW, Reardon AF, Ryabchenko KA, Castillo D, Freund R. A latent class analysis of dissociation and posttraumatic stress disorder: evidence for a dissociative subtype. Arch Gen Psychiatry. 2012;69:698–705. https://doi.org/10.1001/archgenpsychiatry.2011.1574.
Galatzer-Levy IR, Huang SH, Bonanno GA. Trajectories of resilience and dysfunction following potential trauma: a review and statistical evaluation. Clin Psychol Rev. 2018;63:41–55. https://doi.org/10.1016/j.cpr.2018.05.008.
True WR, Rice J, Eisen SA, Heath AC, Goldberg J, Lyons MJ, et al. A twin study of genetic and environmental contributions to liability for posttraumatic stress symptoms. Arch Gen Psychiatry. 1993;50:257–64.
Schultebraucks K, Qian M, Abu-Amara D, Dean K, Laska E, Siegel C, et al. Pre-deployment risk factors for PTSD in active-duty personnel deployed to Afghanistan: a machine-learning approach for analyzing multivariate predictors. Mol Psychiatry. 2020. https://doi.org/10.1038/s41380-020-0789-2.
Schultebraucks K, Galatzer-Levy IR. Machine learning for prediction of posttraumatic stress and resilience following trauma: an overview of basic concepts and recent advances. J Trauma Stress. 2019;32:215–25. https://doi.org/10.1002/jts.22384.
Logue MW, Smith AK, Baldwin C, Wolf EJ, Guffanti G, Ratanatharathorn A, et al. An analysis of gene expression in PTSD implicates genes involved in the glucocorticoid receptor pathway and neural responses to stress. Psychoneuroendocrinology. 2015;57:1–13. https://doi.org/10.1016/j.psyneuen.2015.03.016.
Wingo AP, Almli LM, Stevens JS, Klengel T, Uddin M, Li Y, et al. Corrigendum: DICER1 and microRNA regulation in post-traumatic stress disorder with comorbid depression. Nat Commun. 2016;7:10958. https://doi.org/10.1038/ncomms10958.
Breen MS, Tylee DS, Maihofer AX, Neylan TC, Mehta D, Binder EB, et al. PTSD blood transcriptome mega-analysis: shared inflammatory pathways across biological sex and modes of trauma. Neuropsychopharmacology. 2018;43:469–81. https://doi.org/10.1038/npp.2017.220.
Segman RH, Shefi N, Goltser-Dubner T, Friedman N, Kaminski N, Shalev AY. Peripheral blood mononuclear cell gene expression profiles identify emergent post-traumatic stress disorder among trauma survivors. Mol Psychiatry. 2005;10:500–13. https://doi.org/10.1038/sj.mp.4001636.
Fanselow MS, LeDoux JE. Why we think plasticity underlying Pavlovian fear conditioning occurs in the basolateral amygdala. Neuron. 1999;23:229–32.
Fenster RJ, Lebois LAM, Ressler KJ, Suh J. Brain circuit dysfunction in post-traumatic stress disorder: from mouse to man. Nat Rev Neurosci. 2018;19:535–51. https://doi.org/10.1038/s41583-018-0039-7.
Quirk GJ, Russo GK, Barron JL, Lebron K. The role of ventromedial prefrontal cortex in the recovery of extinguished fear. J Neurosci. 2000;20:6225–31.
Milad MR, Quirk GJ. Neurons in medial prefrontal cortex signal memory for fear extinction. Nature. 2002;420:70–4. https://doi.org/10.1038/nature01138.
Milad MR, Wright CI, Orr SP, Pitman RK, Quirk GJ, Rauch SL. Recall of fear extinction in humans activates the ventromedial prefrontal cortex and hippocampus in concert. Biol Psychiatry. 2007;62:446–54. https://doi.org/10.1016/j.biopsych.2006.10.011.
Corcoran KA, Desmond TJ, Frey KA, Maren S. Hippocampal inactivation disrupts the acquisition and contextual encoding of fear extinction. J Neurosci. 2005;25:8978–87. https://doi.org/10.1523/JNEUROSCI.2246-05.2005.
Lori A, Maddox SA, Sharma S, Andero R, Ressler KJ, Smith AK. Dynamic patterns of threat-associated gene expression in the amygdala and blood. Front Psychiatry. 2018;9:778. https://doi.org/10.3389/fpsyt.2018.00778.
Michopoulos V, Beurel E, Gould F, Dhabhar FS, Schultebraucks K, Galatzer-Levy I, et al. Association of prospective risk for chronic PTSD symptoms with low TNFalpha and IFNgamma concentrations in the immediate aftermath of trauma exposure. Am J Psychiatry 2020;177:58–65. https://doi.org/10.1176/appi.ajp.2019.19010039.
Hinrichs R, van Rooij SJ, Michopoulos V, Schultebraucks K, Winters S, Maples-Keller J, et al. Increased skin conductance response in the immediate aftermath of trauma predicts PTSD risk. Chronic Stress. 2019;3:2470547019844441. https://doi.org/10.1177/2470547019844441.
Schultebraucks K, Shalev AY, Michopoulos V, Grudzen CR, Shin SM, Stevens JS, et al. A validated predictive algorithm of post-traumatic stress course following emergency department admission after a traumatic stressor. Nat Med. 2020;26:1084–8. https://doi.org/10.1038/s41591-020-0951-z.
Galatzer-Levy IR, Ankri Y, Freedman S, Israeli-Shalev Y, Roitman P, Gilad M, et al. Early PTSD symptom trajectories: persistence, recovery, and response to treatment: results from the Jerusalem Trauma Outreach and Prevention Study (J-TOPS). PLoS ONE. 2013;8:e70084.
Bryant RA, Nickerson A, Creamer M, O’Donnell M, Forbes D, Galatzer-Levy I, et al. Trajectory of post-traumatic stress following traumatic injury: 6-year follow-up. Br J Psychiatry. 2015;114:145516.
Association AP diagnostic and statistical manual-text revision (DSM-IV-TRim, 2000). (American Psychiatric Association; 2000).
Foa EB, Rothbaum BO. Treating the trauma of rape: cognitive-behavioral therapy for PTSD. Guilford; 2001.
Falsetti SA, Resnick HS, Resick PA, Kilpatrick DG. The Modified PTSD Symptom Scale: a brief self-report measure of posttraumatic stress disorder. Behav Ther. 1993;16:161–2.
Foa EB, Tolin DF. Comparison of the PTSD symptom scale-interview version and the clinician-administered PTSD scale. J Trauma Stress. 2000;13:181–91. https://doi.org/10.1023/A:1007781909213.
Stevens JS, Ely TD, Sawamura T, Guzman D, Bradley B, Ressler KJ, et al. Childhood maltreatment predicts reduced inhibition-related activity in the rostral anterior cingulate in Ptsd, but not trauma-exposed controls. Depress Anxiety. 2016;33:614–22. https://doi.org/10.1002/da.22506.
Yudko E, Lozhkina O, Fouts A. A comprehensive review of the psychometric properties of the Drug Abuse Screening Test. J Subst Abus Treat. 2007;32:189–98. https://doi.org/10.1016/j.jsat.2006.08.002.
Saunders JB, Aasland OG, Babor TF, de la Fuente JR, Grant M. Development of the alcohol use disorders identification test (AUDIT): WHO collaborative project on early detection of persons with harmful alcohol consumption-II. Addiction. 1993;88:791–804. https://doi.org/10.1111/j.1360-0443.1993.tb02093.x.
Beck AT, Steer RA, Garbin MG. Psychometric properties of the Beck Depression Inventory: twenty-five years of evaluation. Clin Psychol Rev. 1988;8:77–100.
Muthen LK, & Muthen, BO. Mplus user’s guide. 3 ed. Muthen & Muthen; 1998.
Nylund KL, Asparouhov T, Muthen BO. Deciding on the number of classes in latent class analysis and growth mixture modeling: a Monte Carlo simulation study. Struct Equ Modeling. 2007;14:535–69.
Pencea I, Munoz AP, Maples-Keller JL, Fiorillo D, Schultebraucks K, Galatzer-Levy I, et al. Emotion dysregulation is associated with increased prospective risk for chronic PTSD development. J Psychiatr Res. 2020;121:222–8. https://doi.org/10.1016/j.jpsychires.2019.12.008.
Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29:15–21. https://doi.org/10.1093/bioinformatics/bts635.
Liao Y, Smyth GK, Shi W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2014;30:923–30. https://doi.org/10.1093/bioinformatics/btt656.
Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:550. https://doi.org/10.1186/s13059-014-0550-8.
Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic acids Res. 2015;43:e47. https://doi.org/10.1093/nar/gkv007.
Law CW, Chen Y, Shi W, Smyth GK. voom: Precision weights unlock linear model analysis tools for RNA-seq read counts. Genome Biol. 2014;15:R29. https://doi.org/10.1186/gb-2014-15-2-r29.
Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics. 2008;9:559. https://doi.org/10.1186/1471-2105-9-559.
Newman AM, Liu CL, Green MR, Gentles AJ, Feng W, Xu Y, et al. Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015;12:453–7. https://doi.org/10.1038/nmeth.3337.
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81:559–75. https://doi.org/10.1086/519795.
Matsuno H, Ohi K, Hashimoto R, Yamamori H, Yasuda Y, Fujimoto M, et al. A naturally occurring null variant of the NMDA type glutamate receptor NR3B subunit is a risk factor of schizophrenia. PLoS ONE. 2015;10:e0116319. https://doi.org/10.1371/journal.pone.0116319.
Hornig T, Gruning B, Kundu K, Houwaart T, Backofen R, Biber K, et al. GRIN3B missense mutation as an inherited risk factor for schizophrenia: whole-exome sequencing in a family with a familiar history of psychotic disorders. Genet Res. 2017;99:e1. https://doi.org/10.1017/S0016672316000148.
Teschendorff AE, Marabita F, Lechner M, Bartlett T, Tegner J, Gomez-Cabrero D, et al. A beta-mixture quantile normalization method for correcting probe design bias in Illumina Infinium 450 k DNA methylation data. Bioinformatics. 2013;29:189–96. https://doi.org/10.1093/bioinformatics/bts680.
Johnson WE, Li C, Rabinovic A. Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics. 2007;8:118–27. https://doi.org/10.1093/biostatistics/kxj037.
Gillespie CF, Bradley B, Mercer K, Smith AK, Conneely K, Gapen M, et al. Trauma exposure and stress-related disorders in inner city primary care patients. Gen Hosp Psychiatry. 2009;31:505–14. https://doi.org/10.1016/j.genhosppsych.2009.05.003.
Almli LM, Lori A, Meyers JL, Shin J, Fani N, Maihofer AX, et al. Problematic alcohol use associates with sodium channel and clathrin linker 1 (SCLT1) in trauma-exposed populations. Addict Biol. 2017. https://doi.org/10.1111/adb.12569.
Nievergelt C,. Maihofer AX, Koenen KC. International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry- specific genetic risk loci. Nat Commun. 2019;10. https://doi.org/10.1038/s41467-019-12576-w.
Smyth GK. Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol. 2004;3:Article3. https://doi.org/10.2202/1544-6115.1027.
Shabalin AA. Matrix eQTL: ultra fast eQTL analysis via large matrix operations. Bioinformatics. 2012;28:1353–8. https://doi.org/10.1093/bioinformatics/bts163.
Consortium GT. The Genotype-Tissue Expression (GTEx) project. Nat Genet. 2013;45:580–5. https://doi.org/10.1038/ng.2653.
Collado-Torres L, Burke EE, Peterson A, Shin J, Straub RE, Rajpurohit A, et al. Regional heterogeneity in gene expression, regulation, and coherence in the frontal cortex and hippocampus across development and schizophrenia. Neuron 2019;103:203–16. https://doi.org/10.1016/j.neuron.2019.05.013.
McGiffin JN, Galatzer-Levy IR, Bonanno GA. Socioeconomic resources predict trajectories of depression and resilience following disability. Rehabil Psychol. 2019;64:98–103. https://doi.org/10.1037/rep0000254.
Shalev AY, Gevonden M, Ratanatharathorn A, Laska E, van der Mei WF, Qi W.et al; International Consortium to Predict P. Estimating the risk of PTSD in recent trauma survivors: results of the International Consortium to Predict PTSD (ICPP). World Psychiatry. 2019;18:77–87. https://doi.org/10.1002/wps.20608.
McLaughlin KA, Koenen KC, Hill ED, Petukhova M, Sampson NA, Zaslavsky AM, et al. Trauma exposure and posttraumatic stress disorder in a national sample of adolescents. J Am Acad Child Adolesc Psychiatry. 2013;52:815–30. https://doi.org/10.1016/j.jaac.2013.05.011.
Kessler RC, Aguilar-Gaxiola S, Alonso J, Benjet C, Bromet EJ, Cardoso G, et al. Trauma and PTSD in the WHO World Mental Health Surveys. Eur J Psychotraumatol. 2017;8:1353383. https://doi.org/10.1080/20008198.2017.1353383.
Niemann S, Kanki H, Fukui Y, Takao K, Fukaya M, Hynynen MN, et al. Genetic ablation of NMDA receptor subunit NR3B in mouse reveals motoneuronal and nonmotoneuronal phenotypes. Eur J Neurosci. 2007;26:1407–20. https://doi.org/10.1111/j.1460-9568.2007.05774.x.
Bartanusz V, Aubry JM, Pagliusi S, Jezova D, Baffi J, Kiss JZ. Stress-induced changes in messenger RNA levels of N-methyl-D-aspartate and AMPA receptor subunits in selected regions of the rat hippocampus and hypothalamus. Neuroscience. 1995;66:247–52. https://doi.org/10.1016/0306-4522(95)00084-v.
Riaza Bermudo-Soriano C, Perez-Rodriguez MM, Vaquero-Lorenzo C, Baca-Garcia E. New perspectives in glutamate and anxiety. Pharm Biochem Behav. 2012;100:752–74. https://doi.org/10.1016/j.pbb.2011.04.010.
Miglio G, Varsaldi F, Lombardi G. Human T lymphocytes express N-methyl-D-aspartate receptors functionally active in controlling T cell activation. Biochem Biophys Res Commun. 2005;338:1875–83. https://doi.org/10.1016/j.bbrc.2005.10.164.
Nievergelt CM, Maihofer AX, Klengel T, Atkinson EG, Chen CY, Choi KW, et al. International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci. Nat Commun. 2019;2019:4558. https://doi.org/10.1038/s41467-019-12576-w.
Bam M, Yang X, Zumbrun EE, Zhong Y, Zhou J, Ginsberg JP, et al. Dysregulated immune system networks in war veterans with PTSD is an outcome of altered miRNA expression and DNA methylation. Sci Rep. 2016;6:31209. https://doi.org/10.1038/srep31209.
Mehta D, Voisey J, Bruenig D, Harvey W, Morris CP, Lawford B, et al. Transcriptome analysis reveals novel genes and immune networks dysregulated in veterans with PTSD. Brain Behav Immun. 2018;74:133–42. https://doi.org/10.1016/j.bbi.2018.08.014.
Andersson O, Stenqvist A, Attersand A, von Euler G. Nucleotide sequence, genomic organization, and chromosomal localization of genes encoding the human NMDA receptor subunits NR3A and NR3B. Genomics. 2001;78:178–84. https://doi.org/10.1006/geno.2001.6666.
Feder A, Parides MK, Murrough JW, Perez AM, Morgan JE, Saxena S, et al. Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder: a randomized clinical trial. JAMA Psychiatry. 2014;71:681–8. https://doi.org/10.1001/jamapsychiatry.2014.62.
Nair J, Singh, Ajit S. The role of the glutamatergic system in posttraumatic stress disorder. CNS Spectr. 2008;13:585–91. https://doi.org/10.1017/s1092852900016862.
Lin YT, Hsieh MH, Liu CC, Hwang TJ, Chien YL, Hwu HG, et al. A recently-discovered NMDA receptor gene, GRIN3B, is associated with duration mismatch negativity. Psychiatry Res. 2014;218:356–8. https://doi.org/10.1016/j.psychres.2014.04.032.
Sedaghati M, Vousooghi N, Goodarzi A, Yaghmaei P, Mokri A, Zarrindast MR. Expression of NR3B but not NR2D subunit of NMDA receptor in human blood lymphocytes can serve as a suitable peripheral marker for opioid addiction studies. Eur J Pharmacol. 2010;633:50–4. https://doi.org/10.1016/j.ejphar.2010.02.007.
Yu Y, Lin Y, Takasaki Y, Wang C, Kimura H, Xing J, et al. Rare loss of function mutations in N-methyl-D-aspartate glutamate receptors and their contributions to schizophrenia susceptibility. Transl Psychiatry. 2018;8:12. https://doi.org/10.1038/s41398-017-0061-y.
Sadat-Shirazi MS, Vousooghi N, Alizadeh B, Makki SM, Zarei SZ, Nazari S, et al. Expression of NMDA receptor subunits in human blood lymphocytes: a peripheral biomarker in online computer game addiction. J Behav Addict. 2018;7:260–8. https://doi.org/10.1556/2006.7.2018.35.
Bhandage AK, Jin Z, Hellgren C, Korol SV, Nowak K, Williamsson L, et al. NMDA and kainate glutamate receptor subunits are expressed in human peripheral blood mononuclear cells (PBMCs) where the expression of GluK4 is altered by pregnancy and GluN2D by depression in pregnant women. J Neuroimmunol. 2017;305:51–8. https://doi.org/10.1016/j.jneuroim.2017.01.013.
Sadat-Shirazi MS, Ashabi G, Hessari MB, Khalifeh S, Neirizi NM, Matloub M, et al. NMDA receptors of blood lymphocytes anticipate cognitive performance variations in healthy volunteers. Physiol Behav. 2019;201:53–8. https://doi.org/10.1016/j.physbeh.2018.12.015.
Girgenti MJ, Wang J, Ji D, Cruz DA, Traumatic Stress Brain Research G, Stein MB, et al. Transcriptomic organization of the human brain in post-traumatic stress disorder. Nat Neurosci 2021;24:24–33. https://doi.org/10.1038/s41593-020-00748-7.
Irwin RE, Thakur A, ON KM, et al. CP. 5-Hydroxymethylation marks a class of neuronal gene regulated by intragenic methylcytosine levels. Genomics. 2014;104:383–92. https://doi.org/10.1016/j.ygeno.2014.08.013.
Mill J, Tang T, Kaminsky Z, Khare T, Yazdanpanah S, Bouchard L, et al. Epigenomic profiling reveals DNA-methylation changes associated with major psychosis. Am J Hum Genet. 2008;82:696–711. https://doi.org/10.1016/j.ajhg.2008.01.008.
Maunakea AK, Nagarajan RP, Bilenky M, Ballinger TJ, D’Souza C, Fouse SD, et al. Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature. 2010;466:253–7. https://doi.org/10.1038/nature09165.
Shin LM, Rauch SL, Pitman RK. Amygdala, medial prefrontal cortex, and hippocampal function in PTSD. Ann N Y Acad Sci. 2006;1071:67–79. https://doi.org/10.1196/annals.1364.007.
Dahlgren MK, Laifer LM, VanElzakker MB, Offringa R, Hughes KC, Staples-Bradley LK, et al. Diminished medial prefrontal cortex activation during the recollection of stressful events is an acquired characteristic of PTSD. Psychol Med. 2018;48:1128–38. https://doi.org/10.1017/S003329171700263X.
Xie X, Liu H, Zhang J, Chen W, Zhuang D, Duan S, et al. Association between genetic variations of NMDA receptor NR3 subfamily genes and heroin addiction in male Han Chinese. Neurosci Lett. 2016;631:122–5. https://doi.org/10.1016/j.neulet.2016.08.025.
Chantarujikapong SI, Scherrer JF, Xian H, Eisen SA, Lyons MJ, Goldberg J, et al. A twin study of generalized anxiety disorder symptoms, panic disorder symptoms and post-traumatic stress disorder in men. Psychiatry Res. 2001;103:133–45. https://doi.org/10.1016/s0165-1781(01)00285-2.
Duncan LE, Ratanatharathorn A, Aiello AE, Almli LM, Amstadter AB, Ashley-Koch AE, et al. Largest GWAS of PTSD (N=20 070) yields genetic overlap with schizophrenia and sex differences in heritability. Mol Psychiatry. 2018;23:666–73. https://doi.org/10.1038/mp.2017.77.
Misganaw B, Guffanti G, Lori A, Abu-Amara D, Flory JD, Muller S, et al. Polygenic risk associated with post-traumatic stress disorder onset and severity. Transl Psychiatry. 2019;9:165. https://doi.org/10.1038/s41398-019-0497-3.
McLean SA, Ressler K, Koenen KC, Neylan T, Germine L, Jovanovic T, et al. The AURORA Study: a longitudinal, multimodal library of brain biology and function after traumatic stress exposure. Mol Psychiatry. 2020;25:283–96. https://doi.org/10.1038/s41380-019-0581-3.
Mehta D, Klengel T, Conneely KN, Smith AK, Altmann A, Pace TW, et al. Childhood maltreatment is associated with distinct genomic and epigenetic profiles in posttraumatic stress disorder. Proc Natl Acad Sci USA 2013;110:8302–7. https://doi.org/10.1073/pnas.1217750110.
Breen MS, Maihofer AX, Glatt SJ, Tylee DS, Chandler SD, Tsuang MT, et al. Gene networks specific for innate immunity define post-traumatic stress disorder. Mol Psychiatry. 2015;20:1538–45. https://doi.org/10.1038/mp.2015.9.
Kuan PF, Waszczuk MA, Kotov R, Clouston S, Yang X, Singh PK, et al. Gene expression associated with PTSD in World Trade Center responders: an RNA sequencing study. Transl Psychiatry. 2017;7:1297. https://doi.org/10.1038/s41398-017-0050-1.
Acknowledgements
We are grateful to Kimberly Kerley, Becky Hinrichs, Alex O. Rothbaum, Andrew Kimmel, Kammarauche Asuzu, and Raquel Kirmse for their technical assistance in performing experiments, collecting behavioral data, data management, and recruiting. We are grateful to the nurses, physicians, staff, and Emergency Department participants for their time and effort in supporting this research.
Author information
Authors and Affiliations
Contributions
A.L. performed the statistical analyses, analyzed and interpreted the data, and contributed to writing the manuscript. K.S. modeled the growth curve trajectories based on longitudinal PSS symptoms, helped with the statistical analyses, and contributed to editing the manuscript. I.G.-L. modeled the growth curve trajectories based on longitudinal PSS symptoms and contributed to the writing of the manuscript. N.P.D. inferred the cell type proportion, performed statistical analyses, and contributed to the manuscript’s writing. S.K. performed the methylation analyses and contributed to the manuscript’s writing. A.K.S. led the methylation analyses, including collection and processing of the samples, and contributed to the manuscript’s writing. A.J.M. helped to design the experiment, recruit the patients, and edit the manuscript. R.R. and M.H. were involved in processing the blood for RNA analyses, including QC and statistical analyses, and they contributed to the editing of the manuscript. G.G. helped with the expression analyses, and contributed to the manuscript’s editing. S.W. helped to design the experiment, recruit the patients, and write the manuscript. F.G. and P.D.H. helped to design the experiment, recruit the patients, and edit the manuscript. C.B.N. helped to design the experiment, and write the manuscript. T.J., J.L.M.-K., J.S.S., and V.M. helped to design the experiment, recruit the patients, and write the manuscript. B.O.R. helped to design the experiment and write the manuscript. A.P.W. and K.J.R. obtained funding, helped to design the experiment, analyze and interpret the data, supervise other contributors, write the initial manuscript, and edit the final manuscript. E.G. contributed to analyses and writing.
Corresponding authors
Ethics declarations
Competing interests
The data for the analyses described in this manuscript (GRIN3B eQTL variants) were obtained from the GTEx Portal on 12/13/2019. C.B.N discloses the following: Research/Grants: National Institutes of Health (NIH). Consulting (past 12 months): ANeuroTech (division of Anima BV), Signant Health, Sunovion Pharmaceuticals, Inc., Janssen Research and Development LLC, Magstim, Inc., Navitor Pharmaceuticals, Inc., Intra-Cellular Therapies, Inc., EMA Wellness, Acadia Pharmaceuticals, Axsome, Sage, BioXcel Therapeutics, Silo Pharma, XW Pharma, Neuritek, Engrail Therapeutics, and Corcept Therapeutics Pharmaceuticals Company. Stockholder: Xhale, Seattle Genetics, Antares, BI Gen Holdings, Inc., Corcept Therapeutics Pharmaceuticals Company, and EMA Wellness. Scientific Advisory Boards: ANeuroTech (division of Anima BV), Brain and Behavior Research Foundation (BBRF), Anxiety and Depression Association of America (ADAA), Skyland Trail, Signant Health, Laureate Institute for Brain Research (LIBR), Inc., Magnolia CNS, and Heading Health. Board of Directors: Gratitude America, ADAA, and Xhale Smart, Inc. Patents: method and devices for transdermal delivery of lithium (US 6,375,990B1). Method of assessing antidepressant drug therapy via transport inhibition of monoamine neurotransmitters by ex vivo assay (US 7,148,027B2). Speakers Bureau: none. K.J.R. provides fee-for-service consultation for Biogen, Alkermes, and Resilience Therapeutics. He also holds patents for a number of targets related to improving extinction of fear; however, he has received no equity or income within the past 3 years related to these. He receives or has received research funding from NIMH, HHMI, NARSAD, and the Burroughs Wellcome Foundation. B.O.R has funding from Wounded Warrior Project, Department of Defense, National Institute of Mental Health, and McCormick Foundation. B.O.R. receives royalties from Oxford University Press, Guilford, APPI, and Emory University, and has served on recent advisory boards for Aptinyx, Sandoz, and Nobilis. N.P.D. has held a part-time paid position at Cohen Veteran Biosciences. N.P.D. has been a consultant for Sunovion Pharmaceuticals and is on the scientific advisory board for Sentio Solutions, Inc. All remaining authors declare no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
About this article
Cite this article
Lori, A., Schultebraucks, K., Galatzer-Levy, I. et al. Transcriptome-wide association study of post-trauma symptom trajectories identified GRIN3B as a potential biomarker for PTSD development. Neuropsychopharmacol. 46, 1811–1820 (2021). https://doi.org/10.1038/s41386-021-01073-8
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/s41386-021-01073-8
This article is cited by
-
Fear memory regulation by the cAMP signaling pathway as an index of reexperiencing symptoms in posttraumatic stress disorder
Molecular Psychiatry (2024)
-
Post-traumatic stress disorder: clinical and translational neuroscience from cells to circuits
Nature Reviews Neurology (2022)
-
Amygdala DCX and blood Cdk14 are implicated as cross-species indicators of individual differences in fear, extinction, and resilience to trauma exposure
Molecular Psychiatry (2022)
