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Transcriptome-wide association study of post-trauma symptom trajectories identified GRIN3B as a potential biomarker for PTSD development.

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.

SUBMITTER: Lori A

PROVIDER: S-EPMC8357796 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Transcriptome-wide association study of post-trauma symptom trajectories identified GRIN3B as a potential biomarker for PTSD development.

Lori Adriana A Schultebraucks Katharina K Galatzer-Levy Isaac I Daskalakis Nikolaos P NP Katrinli Seyma S Smith Alicia K AK Myers Amanda J AJ Richholt Ryan R Huentelman Matthew M Guffanti Guia G Wuchty Stefan S Gould Felicia F Harvey Philip D PD Nemeroff Charles B CB Jovanovic Tanja T Gerasimov Ekaterina S ES Maples-Keller Jessica L JL Stevens Jennifer S JS Michopoulos Vasiliki V Rothbaum Barbara O BO Wingo Aliza P AP Ressler Kerry J KJ

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20210629 10

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 ...[more]

PMID: 34188182

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Project description:Contemporary symptom-based diagnosis of post-traumatic stress disorder (PTSD) largely overlooks related neurobehavioral mechanisms and relies entirely on subjective interpersonal reporting. Previous studies associating biomarkers with PTSD have mostly used symptom-based diagnosis as the main outcome measure, disregarding the wide variability and richness of PTSD phenotypical features. Here, we aimed to computationally derive potential biomarkers that could efficiently differentiate PTSD subtypes among recent trauma survivors. A three-staged semi-unsupervised method ("3C") was used to firstly categorize individuals by current PTSD symptom severity, then derive clusters based on clinical features related to PTSD (e.g. anxiety and depression), and finally to classify participants' cluster membership using objective multi-domain features. A total of 256 features were extracted from psychometrics, cognitive functioning, and both structural and functional MRI data, obtained from 101 adult civilians (age = 34.80 ± 11.95; 51 females) evaluated within 1 month of trauma exposure. The features that best differentiated cluster membership were assessed by importance analysis, classification tree, and ANOVA. Results revealed that entorhinal and rostral anterior cingulate cortices volumes (structural MRI domain), in-task amygdala's functional connectivity with the insula and thalamus (functional MRI domain), executive function and cognitive flexibility (cognitive testing domain) best differentiated between two clusters associated with PTSD severity. Cross-validation established the results' robustness and consistency within this sample. The neural and cognitive potential biomarkers revealed by the 3C analytics offer objective classifiers of post-traumatic morbidity shortly following trauma. They also map onto previously documented neurobehavioral mechanisms associated with PTSD and demonstrate the usefulness of standardized and objective measurements as differentiating clinical sub-classes shortly after trauma.

Project description:BackgroundRecent years have shown an increased application of prospective trajectory-oriented approaches to posttraumatic stress disorder (PTSD). Although women are generally considered at increased PTSD risk, sex and gender differences in PTSD symptom trajectories have not yet been extensively studied.ObjectiveTo perform an in-depth investigation of differences in PTSD symptom trajectories across one-year post-trauma between men and women, by interpreting the general trends of trajectories observed in sex-disaggregated samples, and comparing within-trajectory symptom course and prevalence rates.MethodWe included N = 554 participants (62.5% men, 37.5% women) from a multi-centre prospective cohort of emergency department patients with suspected severe injury. PTSD symptom severity was assessed at 1, 3, 6, and 12 months post-trauma, using the Clinician-Administered PTSD Scale for DSM-IV. Latent growth mixture modelling on longitudinal PTSD symptoms was performed within the sex-disaggregated whole samples. Bayesian modelling with informative priors was applied for reliable model estimation, considering the imbalanced prevalence of the expected latent trajectories.ResultsIn terms of general trends, the same trajectories were observed for men and women, i.e. resilient, recovery, chronic symptoms and delayed onset. Within-trajectory symptom courses were largely comparable, but resilient women had higher symptoms than resilient men. Sex differences in prevalence rates were observed for the recovery (higher in women) and delayed onset (higher in men) trajectories. Model fit for the sex-disaggregated samples was better than for the whole sample, indicating preferred application of sex-disaggregation. Analyses within the whole sample led to biased estimates of overall and sex-specific trajectory prevalence rates.ConclusionsSex-disaggregated trajectory analyses revealed limited sex differences in PTSD symptom trajectories within one-year post-trauma in terms of general trends, courses and prevalence rates. The observed biased trajectory prevalence rates in the whole sample emphasize the necessity to apply appropriate statistical techniques when conducting sex-sensitive research.

Project description:Background: Network analysis has gained increasing attention as a new framework to study complex associations between symptoms of post-traumatic stress disorder (PTSD). A number of studies have been published to investigate symptom networks on different sets of symptoms in different populations, and the findings have been inconsistent. Objective: We aimed to extend previous research by testing whether differences in PTSD symptom networks can be found in survivors of type I (single event; sudden and unexpected, high levels of acute threat) vs. type II (repeated and/or protracted; anticipated) trauma (with regard to their index trauma). Method: Participants were trauma-exposed individuals with elevated levels of PTSD symptomatology, most of whom (94%) were undergoing assessment in preparation for PTSD treatment in several treatment centres in Germany and Switzerland (n = 286 with type I and n = 187 with type II trauma). We estimated Bayesian Gaussian graphical models for each trauma group and explored group differences in the symptom network. Results: First, for both trauma types, our analyses identified the edges that were repeatedly reported in previous network studies. Second, there was decisive evidence that the two networks were generated from different multivariate normal distributions, i.e. the networks differed on a global level. Third, explorative edge-wise comparisons showed moderate or strong evidence for specific 12 edges. Edges which emerged as especially important in distinguishing the networks were between intrusions and flashbacks, highlighting the stronger positive association in the group of type II trauma survivors compared to type I survivors. Flashbacks showed a similar pattern of results in the associations with detachment and sleep problems (type II > type I). Conclusion: Our findings suggest that trauma type contributes to the heterogeneity in the symptom network. Future research on PTSD symptom networks should include this variable in the analyses to reduce heterogeneity.

Dataset Information

Transcriptome-wide association study of post-trauma symptom trajectories identified GRIN3B as a potential biomarker for PTSD development.

Publications

Transcriptome-wide association study of post-trauma symptom trajectories identified GRIN3B as a potential biomarker for PTSD development.

Similar Datasets

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