Blood-based gene-expression biomarkers of post-traumatic stress disorder among deployed marines: A pilot study

Abstract

The etiology of post-traumatic stress disorder (PTSD) likely involves the interaction of numerous genes and environmental factors. Similarly, gene-expression levels in peripheral blood are influenced by both genes and environment, and expression levels of many genes show good correspondence between peripheral blood and brain tissues. In that context, this pilot study sought to test the following hypotheses: (1) post-trauma expression levels of a gene subset in peripheral blood would differ between Marines with and without PTSD; (2) a diagnostic biomarker panel of PTSD among high-risk individuals could be developed based on gene-expression in readily assessable peripheral blood cells; and (3) a diagnostic panel based on expression of individual exons would surpass the accuracy of a model based on expression of full-length gene transcripts. Gene-expression levels in peripheral blood samples from 50 U.S. Marines (25 PTSD cases and 25 non-PTSD comparison subjects) were determined by microarray following their return from deployment to war-zones in Iraq or Afghanistan. The original sample was carved into training and test subsets for construction of support vector machine classifiers. The panel of peripheral blood biomarkers achieved 80% prediction accuracy in the test subset based on the expression of just two full-length transcripts (GSTM1 and GSTM2). A biomarker panel based on 20 exons attained an improved 90% accuracy in the test subset. Though further refinement and replication of these biomarker profiles are required, these preliminary results provide proof-of-principle for the diagnostic utility of blood-based mRNA-expression in PTSD among trauma-exposed individuals.

Keywords: Alternative splicing; Antioxidant; Biomarker; Diagnosis; Microarray; Oxidative stress; Peripheral blood mononuclear cells; Transcriptome; Trauma; mRNA.

Figure 1

Microarray-derived expression levels (ordinate) of summarized exon probesets reflecting whole-transcript expression levels (abscissa) of glutathione s-transferase mu 1 (GSTM1) and glutathione s-transferase mu 2 (GSTM2) in peripheral blood mononuclear cells from PTSD cases (n=25, red) and comparison subjects (n=25, blue). These transcripts were notably down-regulated among PTSD cases within the full sample (fold changes -1.58 and -2.00, respectively) and were identified as the sole components of the optimal performing SVM classifier of diagnostic status, which achieved 80% accuracy in the test subset (n=10; 4 of 5 cases correctly identified).

Figure 2

Microarray-derived expression levels (ordinate) of individual exon-probes (abscissa) of dynein, cytoplasmic 1, light intermediate chain 1 (DYNC1LI1) in peripheral blood mononuclear cells from PTSD cases (n=25, triangles) and comparison subjects (n=25, squares). The interaction of diagnosis and exon ID was highly significant (p = 6.7E-07, Bonferroni-corrected p = 1.4E-02) owing to the selective down-regulated of an exon (probeset ID 8086013; p = 0.019) in the context of comparable expression levels of all other exons.