Summary: Trauma-exposed veterans with PTSD and comorbid externalizing psychiatric disorders, such as substance abuse or antisocial personality disorder are at greater risk for early death.
Source: Boston University
Psychiatric symptoms and diagnoses increase risk for premature morbidity and mortality.
Now a new study has found that trauma-exposed Veterans with post-traumatic stress disorder and externalizing psychiatric disorders, like substance use disorders and antisocial personality disorder, are at greater risk for early death.
“Our study found that PTSD and comorbid conditions like substance misuse, are associated with a cellular marker of early death found in DNA methylation patterns and referred to as GrimAge” explained corresponding author Erika Wolf, PhD, the study’s senior author, who is a clinical research psychologist for the National Center for PTSD at VA Boston Healthcare System and professor of psychiatry at BUSM.
The study included two different samples of Veterans with trauma exposure and high rates of PTSD and associated psychiatric conditions. They included a group of 434 relatively younger veterans (average age early 30s) who had served in the post-9/11 conflicts and a group of 647 trauma-exposed middle-age veterans and their trauma-exposed spouses (average age early 50s).
Both groups were assessed for a range of psychological conditions and underwent a blood draw to obtain genetic information and to test for levels of a variety of inflammatory and neuropathological molecules.
The younger cohort also underwent cognitive testing and a brain MRI.
The researchers then used the DNA methylation data obtained in each blood sample to measure “GrimAge” using an existing algorithm that is predictive of time to death. They then correlated GrimAge with a range of psychiatric diagnoses, biological markers, cognitive tests and metrics of brain morphology.
In addition to associations between PTSD and externalizing psychiatric disorders with the DNA methylation marker of shortened time-to-death, the study found that the GrimAge DNA methylation index was associated with a number of adverse clinical outcomes, including alterations in inflammation, oxidative stress, immune, and metabolic molecules, and with metrics of neuropathology such as cortical thinning, a blood-based measure of astrocyte damage, and cognitive decline.
“Collectively our findings suggest that a number of psychiatric disorders may increase risk for early death and underscore the importance of identification of those at greatest risk,” said Wolf.
According to her, the biomarkers associated with GrimAge could hold the key to identification of new biological treatments to slow or reverse the march towards premature death among those with symptoms of traumatic stress.
“The ability to detect low levels of these molecules years before they may become clinically significant and hopefully be able to intervene early on in disease trajectories is critical for efforts to ultimately slow or reverse the adverse health consequences of traumatic stress.”
The study’s first author was Sage Hawn, PhD, who was an NIMH-funded T-32 post-doctoral fellow in the department of psychiatric at BUSM and the National Center for PTSD when she completed this work.
These finding appear online in the journal Translational Psychiatry.
Funding: Funding for this study was provided by: Merit Review Award Number I01 CX-001276-01 from United States (U.S.) Department of Veterans Affairs Clinical Sciences R&D (CSRD) Service, the National Institute on Aging of the National Institutes of Health under Award Number RF1AG068121, and the National Institute of Mental Health under Award Numbers R21MH102834 and 5T32MH019836. This work was also supported by the Translational Research Center for TBI and Stress Disorders (TRACTS), a VA Rehabilitation Research and Development Traumatic Brain Injury Center of Excellence (B9254-C), and the Cooperative Studies Program, Department of Veterans Affairs.
This research is the result of work supported with resources and the use of facilities at the Pharmacogenomics Analysis Laboratory, Research and Development Service, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, and the National Center for PTSD.
For whom the bell tolls: psychopathological and neurobiological correlates of a DNA methylation index of time-to-death
Psychopathology is a risk factor for accelerated biological aging and early mortality.
We examined associations between broad underlying dimensions of psychopathology (reflecting internalizing and externalizing psychiatric symptoms), PTSD, and age-adjusted GrimAge (“GrimAge residuals”), a DNA methylation biomarker of mortality risk relative to age.
We also examined neurobiological correlates of GrimAge residuals, including neurocognitive functioning, blood-based biomarkers (of inflammation, neuropathology, metabolic disease), and cortical thickness. Data from two independent trauma-exposed military cohorts (n = 647 [62.9% male, Mage = 52], n = 434 [90% male, Mage = 32]) were evaluated using linear regression models to test associations between GrimAge residuals, psychopathology, and health correlates.
Externalizing psychopathology significantly predicted GrimAge residuals in both cohorts (ps < 0.028). PTSD predicted GrimAge residuals in the younger (p = 0.001) but not the older cohort. GrimAge residuals were associated with several neurobiological variables available in the younger cohort, including cognitive disinhibition (padj = 0.021), poorer memory recall (padj = 0.023), cardiometabolic pathology (padj < 0.001), oxidative stress (padj = 0.003), astrocyte damage (padj = 0.021), inflammation (C-reactive protein: padj < 0.001; IL-6: padj < 0.001), and immune functioning (padj < 0.001).
A subset of inflammatory and neuropathology analytes were available in the older cohort and showed associations with GrimAge residuals (IL-6: padj < 0.001; TNF-α: padj < 0.001).
GrimAge residuals were also associated with reduced cortical thickness in right lateral orbitofrontal cortex (padj = 0.018) and left fusiform gyrus (padj = 0.030), which are related to emotion regulation and facial recognition, respectively.
Psychopathology may be a common risk factor for elevated mortality risk. GrimAge could help identify those at risk for adverse health outcomes and allow for early disease identification and treatment.