The National Research Action Plan (NRAP) (2013) called attention to the alarmingly high rates of combat-related PTSD observed among service members and veterans deployed in support of the wars in Iraq and Afghanistan. As a result, the Consortium to Alleviate PTSD (CAP) was formed to a) significantly advance treatment strategies for PTSD including interventions for early, chronic, and latent onset cases, and b) to identify and confirm clinically relevant biomarkers as diagnostic and prognostic indicators of PTSD and co-occurring disorders. This project aims to fill gaps identified in the NRAP by examining the validity of genetic-based biomarkers to identify PTSD, PTSD course, and response to PTSD treatment. We plan to leverage extensive existing resources in the STRONG STAR Repository to examine a comprehensive set of genetic and epigenetic markers associated with PTSD. These resources include: (1) a collection of human postmortem tissue of PTSD (n=30) and matched control (n=60) brains; (2) a cohort of service members treated for PTSD with blood collected prior to treatment and at 6 months post-treatment (n=600); and (3) an epidemiologic cohort of Soldiers assessed prior to and after deployment in support of Operations Enduring Freedom, Iraqi Freedom and New Dawn that included blood collection and PTSD assessment at each assessment (n=4,112). Using a combination of whole-genome microarray and sequencing approaches, we will: (1) identify genetic (SNP, mRNA) or epigenetic (DNA methylation, microRNA) alterations in PTSD; (2) characterize the neuronal morphology of selected brain regions in PTSD and matched controls through Golgi impregnation; (3) identify top gene regulatory networks among the identified set of genes across the samples to guide biomarker analyses; and (4) systematically identify, validate, and test biomarkers based on the mRNA, SNPs, DNA methylation, and microRNA markers of identified genes. We have assembled a collaborative team of scientists consisting of a genetic epidemiologist (Dr. Williamson), a psychiatric geneticist (Dr. Gelernter), a geneticist (Dr. Carless), a neuroanatomist (Dr. Selemon), human postmortem experts (Drs. Young, Kleinman, Hyde, Thompson, & Cruz), biostatisticians (Drs. Mintz, Gelfond, Michelek, & Jaffe), and a clinical psychologist (Dr. Litz). In addition, we propose to collaborate with the DoD Integrated Systems Biology group (Drs. Jett & Hammamieh) to leverage SysBioCube in order to gain a systems level perspective of our ?-omics? data that will in turn guide our biomarker discovery work. It is expected that this project will be an important first step in filling the genomic and biomarker gaps in PTSD identified by the NRAP and facilitate the development of diagnostic and prognostic biomarker panels to aid in the detection, treatment, and prevention of PTSD.
Gaps in genomics and biomarker research are emphasized in recent Institute of Medicine reports on the state of research on military-related PTSD and the National Research Action Plan. The mandate underscores the need for biomarker research that identifies causal mechanisms for disease onset and progression as well as the need to discover new diagnostic methods and treatment targets. In this project, we will evaluate genetic and epigenetic diagnostic and prognostic markers of PTSD. Our specific goals are to identify classes of biomarkers that: (1) Detect the presence of PTSD; (2) Determine who successfully responds to treatment; and (3) Identify individuals at risk for delayed and chronic trajectories of PTSD.
