DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Genetic and Environmental Predictors of Combat-Related PTSD/The STRONG STAR Multidisciplinary PTSD Research Consortium

Posted October 18, 2017

Douglas E. Williamson, Ph.D., Duke University, Durham VA Medical Center, and the University of Texas Health Science Center at San Antonio

Dr. Douglas E. Williamson

Dr. Douglas E. Williamson

Combat-related post-traumatic stress disorder (PTSD) is a chronic and disabling condition associated with substantial impairment and lifelong complications for military Veterans. Recent studies have estimated that one out of every six returning Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF) veterans present with symptoms of PTSD. Given recent deployment rates to Iraq and Afghanistan, combat-related PTSD is likely to have a major public health impact over the next several decades. The healthcare burden of PTSD will be particularly important for the VA as approximately 30% of newly enrolled Veterans between 2002 and 2012 meet the diagnostic criteria for PTSD.

The Department of Defense (DoD) Task Force on Mental Health and the Institute of Medicine released reports in 2007 documenting the urgent need for basic and clinical research focused around combat-related PTSD. To address this problem, the DoD granted over $46 million (M) to establish a consortium focused on PTSD. Funded by a 2007 PTSD Multidisciplinary Research Consortium Award from the PTSD and Traumatic Brain Injury Research Program, the South Texas Research Organization Network Guiding Studies on Trauma and Resilience (STRONG STAR) is a multidisciplinary research consortium composed of 100 collaborating investigators at 20 institutions that are dedicated to evaluating screening, detection, diagnosis, treatment, and intervention methods for PTSD patients. The STRONG STAR team is made up of more than 150 military, civilian, and VA investigators and clinicians. The consortium is centered at the University of Texas Health Science Center, San Antonio, and is also embedded within nearby Fort Hood, where they coordinate recruitment of human subjects with other military and Veteran locations for collaborating investigators from across the country. Together, the STRONG STAR consortium has completed 14 projects, including retrospective data analysis, epidemiological and biological studies, as well as 8 clinical studies.

As part of the consortium, five research cores were established: the administrative core, the assessment core, the data core, the neuroimaging core, and the genomics core. Complementary studies are focused on the root causes of PTSD, including the biological factors that influence PTSD susceptibility and recovery; the influence of comorbid physical and psychological ailments; and the interaction of cognitive-behavioral therapies and pharmacologic treatments. More information on the research currently being done within these main cores can be found on the STRONG STAR website.

The STRONG STAR consortium’s Genomics and Basic Science Core (GBSC) is conducting several integrated studies that are seeking to evaluate the interaction of clinical symptoms and syndromes associated with PTSD. The ultimate goal of the GBSC is to identify genetic variants and biological markers that will: (1) predict the onset of PTSD, (2) influence the expression of PTSD, and (3) monitor patients’ responses to treatment. There is strong evidence that genetics are involved in the risk of developing PTSD and associated comorbidities, such as major depressive disorder.

One particular GBSC study led by Dr. Douglas E. Williamson of Duke University and the Durham VA Medical Center sought to determine specific genetic factors that will enable pre-exposure screening of military personnel who are most at risk of developing PTSD. In this prospective descriptive study, Dr. Williamson’s team examined the behavior and biomarkers of 4,112 active duty soldiers prior to deployment to Iraq and Afghanistan. This pre-deployment screening included behavioral assessments and collection of DNA, RNA, and plasma. The same information was collected from 2,123 soldiers following deployment to determine which genes and changes in their expression were associated with the onset of PTSD. This study was completed in August 2016 and identified novel genes (GRM7 and OXSR1, both on chromosome 3) that are associated with the presence of PTSD. GRM7, the Glutamate Metabotropic Receptor 7, was found to be associated with the presence of significant PTSD symptoms, and contained SNPs associated with initial treatment response. OXSR1, the Oxidative Stress Response 1 gene, was associated with the presence of lifetime PTSD. In addition, the study identified a gene (Disco Interacting Protein 2 Homolog B, DIP2B) that is down-regulated and another gene (SET Binding Protein 1, SETBP1) that is up-regulated after deployment among soldiers who developed a new-onset PTSD. Dr. Williamson and his team also observed SETBP1 to be associated with a reduction of functional spine densities in postmortem tissue. DIP2B plays a critical role in DNA methylation and may therefore impact critical neural circuits underlying the onset of PTSD. In addition, the GBSC developed the STRONG STAR Biorepository to provide support for the collection, processing, analysis, and storage of pre-/post-deployment and pre-/post-treatment biological samples and derived biomarkers of risk for PTSD.

Dr. Williamson’s research will enable psychologists and physicians to analyze naturalistic observation data, better identify and predict treatment outcomes, and help design future PTSD prevention and intervention studies. Specifically, the genes associated with the presence of PTSD and prediction of initial onset may lead to targeted protection from acquiring PTSD or its reversal. This study may also advance future research to uncover biomarkers involved in treatment response that may lead to personalized medicine applications for PTSD. Several forthcoming peer-reviewed scientific articles will describe the genetic association of PTSD and initial treatment response, changes in gene expression following exposure to combat trauma, and moderators and mediators of PTSD symptom trajectories across the deployment cycle.

Links:

Public and Technical Abstracts: The STRONG STAR Multidisciplinary PTSD Research Consortium

STRONG STAR

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Last updated Wednesday, October 18, 2017