For whom the bell tolls: psychopathological and neurobiological correlates of a DNA methylation index of time-to-death

Abstract

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, M_age = 52], n = 434 [90% male, M_age = 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 (p_adj = 0.021), poorer memory recall (p_adj = 0.023), cardiometabolic pathology (p_adj < 0.001), oxidative stress (p_adj = 0.003), astrocyte damage (p_adj = 0.021), inflammation (C-reactive protein: p_adj < 0.001; IL-6: p_adj < 0.001), and immune functioning (p_adj < 0.001). A subset of inflammatory and neuropathology analytes were available in the older cohort and showed associations with GrimAge residuals (IL-6: p_adj < 0.001; TNF-α: p_adj < 0.001). GrimAge residuals were also associated with reduced cortical thickness in right lateral orbitofrontal cortex (p_adj = 0.018) and left fusiform gyrus (p_adj = 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.

Fig. 1. Significant whole brain cortical thickness results.

In a whole brain cortical thickness analysis with a vertex-wise threshold of p < 0.0001 and cluster corrected at p < 0.05, results revealed that there was a significant negative association between GrimAge residuals and the left fusiform gyrus. The color bar indicates the log 10 value for p values associated with the cluster-corrected results. LH = left hemisphere.