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Researchers Link Innate Immune Function to PTSD Development Risk

NEW YORK (GenomeWeb) – Researchers from the US and the UK have linked gene networks involved in innate immunity to post-traumatic stress disorder.

As they reported today in Molecular Psychiatry, researchers led by the University of Southampton's Christopher Woelk analyzed gene expression patterns in peripheral blood samples obtained from US Marines before and after combat deployment, some of whom developed PTSD. Through this, Woelk and his colleagues linked gene networks involved in the regulation of innate immune function and interferon signaling to PTSD. This, the researchers added, could pave the way for preventive measures and better detection of the disorder.

"By comparing US Marines who develop PTSD symptoms to those who do not, we can measure differences in genes, but also take into consideration the dynamic relationships between and among them, their connectivity," first author Michael Breen from Southampton said in a statement. "Because PTSD is thought to be such a complex disorder, measuring these dynamic relationships is crucial to better understanding the PTSD pathology."

PTSD affects between 7 percent and 8 percent of the general US population, the researchers noted, adding that it is estimated to affect some 20 percent of troops returning from the wars in Afghanistan and Iraq.

As part of the larger Marine Resiliency Study, Woelk, Breen, and their colleagues gathered blood samples from 124 male Marines one month before deployment and three months after returning for RNA-seq analysis. At the same time, the Marines were assessed using a structured diagnostic interview for PTSD.

The researchers divided their cohort into 47 cases — those who developed PTSD after deployment — and 47controls. Using RNA-seq data from each, the researchers constructed gene co-expression networks.

The gene co-expression network of post-deployment RNA-seq data consisted of nine modules. Two of those modules, dubbed M1A and M1B, were enriched for genes that were differentially expressed between PTSD cases and controls.

Module M1B, the researchers reported, was more highly expressed in the control group and was linked to resiliency and negatively correlated with PTSD interview score. Genes in this module that were overexpressed in controls were associated with hemostasis, platelet activation, and wound healing, the researchers said. Further, the top five hub genes — C6orf25, CTDSPL, ITGB3, PRKAR2B, and TUBB1— were all linked to hemostasis, especially platelet regulation and function.

Meanwhile, module M1A was more highly expressed among the individuals of the PTSD group and was linked with PTSD interview criteria of avoidance and re-experiencing. Genes in this module that were overexpressed were linked to immune response, especially innate responses governed by interferon signaling. The top five hub genes of this module — IFI35, IFIH1, PARP14, RSAD2, and UBE2L6 — are all interferon-stimulated genes, the researchers noted.

Similarly, by turning to a network analysis of pre-deployment samples, the researchers uncovered a module, called M2A, that was enriched for differentially expressed genes between Marines with and without PTSD before they were even deployed. These module genes were more highly expressed among Marines who developed PTSD and included genes involved in interferon signaling like DTX3L, IFIH1, IFIT3, PARP14, and STAT2.

"What's interesting is that molecular signatures of innate immunity and interferon signaling were identified both after developing PTSD as well as before developing PTSD," noted co-author Dewleen Baker from the University of California, San Diego.

The researchers also drew on a second, independent group of 48 Marines to validate these findings.

This, the researchers said, implicates co-expressed genes linked to innate immune response and interferon signaling in the development of PTSD.

"Since our causal (pre-deployment) and consequential (post-deployment) discoveries are based upon peripheral blood samples, these results suggest that identifying individuals at risk for PTSD development may be achievable through high-throughput profiling of molecular data," added Woelk.

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