PTSD, major depression, and advanced transcriptomic age in brain tissue

Abstract

Background: Psychiatric disorders have been associated with advanced epigenetic age in DNA methylation, yet this relationship has not been studied in the brain transcriptome. We examined transcriptomic age using an RNA-based algorithm recently developed by Ren and Kuan ("RNAAgeCalc") and the associations between posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and alcohol use disorder with age-adjusted RNA age ("RNA age residuals") in three brain regions: dorsolateral prefrontal cortex, ventromedial prefrontal cortex (vmPFC), and motor cortex.Methods: RNA sequencing was used to measure gene expression in postmortem brain tissue from the VA National PTSD Brain Bank (n = 94; 59% male).Results: Linear models revealed that diagnoses of PTSD and/or MDD were positively associated with RNA age residuals in vmPFC only (p-adj = 0.012). Three genes in the RNAAgeCalc algorithm (KCNJ16, HYAL2, and CEBPB) were also differentially expressed in association with PTSD/MDD in vmPFC (p-adj = 6.45E−05 to 0.02). Enrichment analysis revealed that inflammatory and immune-related pathways were overrepresented (p-adj < 0.05) among the 43 genes in RNAAgeCalc that were also at least nominally associated with PTSD/MDD in vmPFC relative to the 448 RNAAgeCalc genes. Endothelial and mural cells were negatively associated with RNA age residuals in vmPFC (both p-adj = 0.028) and with PTSD/MDD (both p-adj = 0.017).Conclusions: Results highlight the importance of inflammation and immune system dysregulation in the link between psychopathology and accelerated cellular aging and raise the possibility that blood−brain barrier degradation may play an important role in stress-related accelerated brain aging.

Decoding the role of transcriptomic clocks in the human prefrontal cortex

“…In the analysis of the knowledge primed deep neural clock, we have to split the sample into a training and testing set, thus reducing our sample size to perform associations with the phenotypic traits. Still, our cohort is larger than similar to recent work 44 . Also, this reduction in sample size did not allow us to stratify the sample by sex to potential sex-specific effects.…”

“…For instance, a previous study using RNAAgeCalc identified an accelerated transcriptional age in 324 World Trade Center responders 50 . Further, an epigenetic age acceleration in the motor cortex 51 and transcriptomic age acceleration in the ventromedial PFC has been reported in PTSD cases 44 . These findings suggest that individuals diagnosed with PTSD exhibit accelerated aging, reflected at both the transcriptomic and epigenomic levels.…”

“…The copyright holder for this preprint this version posted April 25, 2023. ; https://doi.org/10.1101/2023.04. 19.23288765 doi: medRxiv preprint important given recent evidence showing age-associated transcriptomic changes in the PFC involving, for example, gene dysregulation of synaptic genes [40][41][42][43][44] .…”

Association between Perceived Health-Related Quality of Life and Depression with Frailty in the FRASNET Study

“…Of importance, the dysregulated inflammatory state of the elderly (also known as “inflammaging”) is a well-characterized risk factor for chronic conditions such as sarcopenia and depression [ 16 , 17 ] while genes and inflammatory pathways associated with depressive symptoms are being actively studied in the elderly. The findings revealing a link between inflammation, immune dysregulation, and accelerated cellular aging could be relevant to the association we describe [ 18 ].…”