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

• Published in: Neuropsychopharmacology (New York, N.Y.) N.Y.), 2021-09, Vol.46 (10), p.1811-1820
• Main Authors: Lori, Adriana, Schultebraucks, Katharina, Galatzer-Levy, Isaac, Daskalakis, Nikolaos P, Katrinli, Seyma, Smith, Alicia K, Myers, Amanda J, Richholt, Ryan, Huentelman, Matthew, Guffanti, Guia, Wuchty, Stefan, Gould, Felicia, Harvey, Philip D, Nemeroff, Charles B, Jovanovic, Tanja, Gerasimov, Ekaterina S, Maples-Keller, Jessica L, Stevens, Jennifer S, Michopoulos, Vasiliki, Rothbaum, Barbara O, Wingo, Aliza P, Ressler, Kerry J
• Format: Article
• Language: English
• Subjects: Biomarkers; Blood levels; Emergency medical care; Gene expression; Genetic diversity; Glutamic acid receptors (ionotropic); Humans; N-Methyl-D-aspartic acid receptors; Post traumatic stress disorder; Quantitative trait loci; Stress Disorders, Post-Traumatic - genetics; Transcriptome; Transcriptomes; Trauma
• ISSN: 0893-133X; 1740-634X; 1740-634X
• DOI: 10.1038/s41386-021-01073-8

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.