Transcriptome-wide association study of post-trauma symptom trajectories identified GRIN3B as a potential biomarker for PTSD development.
Journal
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
ISSN: 1740-634X
Titre abrégé: Neuropsychopharmacology
Pays: England
ID NLM: 8904907
Informations de publication
Date de publication:
09 2021
09 2021
Historique:
received:
11
12
2020
accepted:
24
05
2021
revised:
26
04
2021
pubmed:
1
7
2021
medline:
28
8
2021
entrez:
30
6
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34188182
doi: 10.1038/s41386-021-01073-8
pii: 10.1038/s41386-021-01073-8
pmc: PMC8357796
doi:
Substances chimiques
Biomarkers
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1811-1820Subventions
Organisme : NIMH NIH HHS
ID : R01 MH094757
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR000424
Pays : United States
Organisme : NICHD NIH HHS
ID : R01 HD102974
Pays : United States
Organisme : NIMH NIH HHS
ID : R21 MH106902
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH094759
Pays : United States
Organisme : NIMH NIH HHS
ID : U01 MH110925
Pays : United States
Informations de copyright
© 2021. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.
Références
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 .
doi: 10.2147/NDT.S10389
pubmed: 21552319
pmcid: 3083990
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 .
doi: 10.1001/archgenpsychiatry.2011.127
pubmed: 21969418
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 .
doi: 10.4088/JCP.13m08715
pubmed: 25188543
pmcid: 4293026
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 .
doi: 10.1001/archpsyc.62.6.593
pubmed: 15939837
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 .
doi: 10.1001/archgenpsychiatry.2011.1574
pubmed: 22752235
pmcid: 3390764
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 .
doi: 10.1016/j.cpr.2018.05.008
pubmed: 29902711
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.
doi: 10.1001/archpsyc.1993.01820160019002
pubmed: 8466386
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 .
doi: 10.1002/jts.22384
pubmed: 30892723
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 .
doi: 10.1016/j.psyneuen.2015.03.016
pubmed: 25867994
pmcid: 4437870
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 .
doi: 10.1038/ncomms10958
pubmed: 26936533
pmcid: 4782056
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 .
doi: 10.1038/npp.2017.220
pubmed: 28925389
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 .
doi: 10.1038/sj.mp.4001636
pubmed: 15685253
Fanselow MS, LeDoux JE. Why we think plasticity underlying Pavlovian fear conditioning occurs in the basolateral amygdala. Neuron. 1999;23:229–32.
doi: 10.1016/S0896-6273(00)80775-8
pubmed: 10399930
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 .
doi: 10.1038/s41583-018-0039-7
pubmed: 30054570
pmcid: 6148363
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.
doi: 10.1523/JNEUROSCI.20-16-06225.2000
pubmed: 10934272
pmcid: 6772571
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 .
doi: 10.1038/nature01138
pubmed: 12422216
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 .
doi: 10.1016/j.biopsych.2006.10.011
pubmed: 17217927
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 .
doi: 10.1523/JNEUROSCI.2246-05.2005
pubmed: 16192388
pmcid: 6725608
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 .
doi: 10.3389/fpsyt.2018.00778
pubmed: 30705647
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 .
doi: 10.1176/appi.ajp.2019.19010039
pubmed: 31352811
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 .
doi: 10.1038/s41591-020-0951-z
pubmed: 32632194
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.
doi: 10.1371/journal.pone.0070084
pubmed: 23990895
pmcid: 3750016
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 .
doi: 10.1023/A:1007781909213
pubmed: 10838669
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 .
doi: 10.1002/da.22506
pubmed: 27062552
pmcid: 4930398
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 .
doi: 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 .
doi: 10.1111/j.1360-0443.1993.tb02093.x
pubmed: 8329970
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.
doi: 10.1016/0272-7358(88)90050-5
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.
doi: 10.1080/10705510701575396
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 .
doi: 10.1016/j.jpsychires.2019.12.008
pubmed: 31865212
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 .
doi: 10.1093/bioinformatics/bts635
pubmed: 23104886
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 .
doi: 10.1093/bioinformatics/btt656
pubmed: 24227677
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 .
doi: 10.1186/s13059-014-0550-8
pubmed: 25516281
pmcid: 4302049
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 .
doi: 10.1093/nar/gkv007
pubmed: 25605792
pmcid: 4402510
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 .
doi: 10.1186/gb-2014-15-2-r29
pubmed: 24485249
pmcid: 4053721
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 .
doi: 10.1186/1471-2105-9-559
pubmed: 19114008
pmcid: 2631488
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 .
doi: 10.1038/nmeth.3337
pubmed: 25822800
pmcid: 4739640
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 .
doi: 10.1086/519795
pubmed: 17701901
pmcid: 1950838
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 .
doi: 10.1371/journal.pone.0116319
pubmed: 25768306
pmcid: 4358936
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 .
doi: 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 .
doi: 10.1093/bioinformatics/bts680
pubmed: 23175756
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 .
doi: 10.1093/biostatistics/kxj037
pubmed: 16632515
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 .
doi: 10.1016/j.genhosppsych.2009.05.003
pubmed: 19892208
pmcid: 2785858
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 .
doi: 10.1093/bioinformatics/bts163
pubmed: 22492648
pmcid: 3348564
Consortium GT. The Genotype-Tissue Expression (GTEx) project. Nat Genet. 2013;45:580–5. https://doi.org/10.1038/ng.2653 .
doi: 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 .
doi: 10.1016/j.neuron.2019.05.013
pubmed: 31174959
pmcid: 7000204
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 .
doi: 10.1037/rep0000254
pubmed: 30570333
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 .
doi: 10.1016/j.jaac.2013.05.011
pubmed: 23880492
pmcid: 3724231
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 .
doi: 10.1080/20008198.2017.1353383
pubmed: 29075426
pmcid: 5632781
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 .
doi: 10.1111/j.1460-9568.2007.05774.x
pubmed: 17880385
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 .
doi: 10.1016/0306-4522(95)00084-v
pubmed: 7477869
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 .
doi: 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 .
doi: 10.1016/j.bbrc.2005.10.164
pubmed: 16289038
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 .
doi: 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 .
doi: 10.1038/srep31209
pubmed: 27510991
pmcid: 4980621
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 .
doi: 10.1016/j.bbi.2018.08.014
pubmed: 30189241
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 .
doi: 10.1006/geno.2001.6666
pubmed: 11735224
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 .
doi: 10.1001/jamapsychiatry.2014.62
pubmed: 24740528
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 .
doi: 10.1017/s1092852900016862
pubmed: 18622363
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 .
doi: 10.1016/j.psychres.2014.04.032
pubmed: 24814139
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 .
doi: 10.1016/j.ejphar.2010.02.007
pubmed: 20153313
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 .
doi: 10.1038/s41398-017-0061-y
pubmed: 29317596
pmcid: 5802496
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 .
doi: 10.1556/2006.7.2018.35
pubmed: 29788757
pmcid: 6174581
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 .
doi: 10.1016/j.jneuroim.2017.01.013
pubmed: 28284346
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 .
doi: 10.1016/j.physbeh.2018.12.015
pubmed: 30553898
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 .
doi: 10.1038/s41593-020-00748-7
pubmed: 33349712
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 .
doi: 10.1016/j.ygeno.2014.08.013
pubmed: 25179375
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 .
doi: 10.1016/j.ajhg.2008.01.008
pubmed: 18319075
pmcid: 2427301
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 .
doi: 10.1038/nature09165
pubmed: 20613842
pmcid: 3998662
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 .
doi: 10.1196/annals.1364.007
pubmed: 16891563
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 .
doi: 10.1017/S003329171700263X
pubmed: 28893331
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 .
doi: 10.1016/j.neulet.2016.08.025
pubmed: 27542340
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 .
doi: 10.1016/s0165-1781(01)00285-2
pubmed: 11549402
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 .
doi: 10.1038/mp.2017.77
pubmed: 28439101
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 .
doi: 10.1038/s41398-019-0497-3
pubmed: 31175274
pmcid: 6555815
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 .
doi: 10.1073/pnas.1217750110
pubmed: 23630272
pmcid: 3657772
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 .
doi: 10.1038/s41398-017-0050-1
pubmed: 29249826
pmcid: 5802695