The 411 on a Blood-based Diagnostic for PTSD

Combining multi-omics and wisdom of crowds analysis investigators identify 28 biomarkers indicative of stress disorder in combat veterans.
A multi-omics analysis from the PTSD Systems Biology Consortium suggests that a set of 28 biomarkers might aid in diagnosing post-traumatic stress disorder (PTSD) in war veterans.
A number of factors—stigma, biases in self-disclosure of symptoms and limitations associated with identifying at-risk individuals—make it a challenge to diagnose PTSD in veterans and active duty soldiers, senior study author Charles Marmar, MD, director of the PTSD Research Program at NYU Langone Health, told CLN Stat. “Prior studies suggest that PTSD may be a systemic illness, affecting not just the brain but the entire body. Therefore, disease signals likely span multiple biological domains, including genes, proteins, cells, tissues, and organism-level physiological changes,” Marmar and his colleagues wrote in Molecular Psychiatry. Previous studies had some success in identifying predictive and diagnostic markers but involved smaller cohorts and a narrower focus with respect to molecular data.
To seek out PTSD-specific biomarker candidates, investigators recruited Operation Enduring Freedom  and/or Operation Iraqi Freedom male veterans spanning ages 20-60, who met criteria for PTSD-positive or PTSD-negative groups. They identified 1 million molecular, cellular, physiological, and clinical features from these veterans, who were grouped into discovery, recall, and validation cohorts. The first group, a discovery cohort of 83 individuals with warzone-related PTSD and 82 warzone-exposed control veterans, was used to identify 343 candidate biomarkers.
The investigators employed a “wisdom of crowds” method of data analysis, an approach often used in financial modeling. Hypothesis, hybrid, and other approaches helped identify the candidate markers from a larger pool of measured blood analytes. In each participant, the researchers assayed for blood-based analytes not only using routine clinical lab panels but also assessing DNA methylation, proteomics, metabolomics, miRNAs, small molecule, and endocrine markers. In another step, they recorded the participants’ physiological measures and computed nonlinear marker combinations.
Using data from recalled participants and a two-stage down-selection process, they further narrowed their panel to 28 final robust and diverse candidate biomarkers for diagnosing PTSD, which cover five of the six molecular data types the researchers were interrogating, including DNA methylation, physiology, miRNA, clinical lab measures, and metabolites. Several biomarkers, such as elevated heart rate and decreased level of coagulation factors, had been associated with PTSD in prior studies. Others have a link to anxiety, major depressive disorder (MDD), and comorbid conditions such as insulin resistance, platelet volume, PDE9A expression, and alterations in the SHANK2 gene. The investigators called out the miRNAs that made the panel, noting that they “reflect the diverse pathology and comorbidities present in PTSD populations, including connections to metabolic diseases and cardiovascular conditions.”
Another independent cohort that validated the 28 features found that 35% of PTSD cases met criteria for MDD. Overall, the 28 biomarkers predicted a PTSD diagnosis in this cohort with 81% accuracy, 85% sensitivity, and 77% specificity. These findings point to the promise of a blood-based screening or diagnostic tool for PTSD, according to Marmar.
PTSD has often been linked to conditions such as depression, anxiety, alcoholism, substance abuse, diabetes, and cardiovascular disease. In the investigators’ view, “a robust PTSD biomarker panel should be specific to PTSD and not any of these or other comorbidities, and able to detect PTSD in both the presence and absence of these comorbid conditions,”—a goal that will require further study.
Marmar told CLN Stat he and his colleagues plan to expand upon these findings by examining other groups such as a larger male veteran cohort, as well as female veterans and civilian victims of trauma. “We also are going to work closely with the Food and Drug Administration to determine if what we have discovered in this study can have some early application to the clinical setting,” he added.
The goal is to make it easier and more objective for physicians to diagnose PTSD so that treatment can be administered earlier when it has its greatest effectiveness, Marmar said.
Another genome-wide association study found a strong genetic tie to PTSD, reporting that its heritability behaves in a manner similar to other forms of mental illness. Examining a large and diverse cohort of 200,000 individuals, researchers from the University of California San Diego School of Medicine and institutions with the Psychiatric Genomics Consortium found that heritability accounts for 5% to up to 20% of PTSD risk variability following trauma. The trial uncovered six loci with a strong link to PTSD risk. Three of the six were only found in men: Two were associated with European ancestry and one in African ancestry.
Looking at genetic associations between PTSD and 235 other disorders, behaviors, and physical traits, the researchers discovered that PTSD overlaps with 21 disorders, including depression, schizophrenia, neuroticism, insomnia, asthma, and coronary artery disease. “Similar to other mental disorders, the genetic contribution to PTSD correlates with that for many other traits," said senior author Karestan Koenen, PhD, associate member of the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard in a statement. “Further research is needed to determine what this means—whether some of the same genes that influence risk for PTSD also influence risk for other diseases like, for example, depression.”