Gene expression correlates of advanced epigenetic age and psychopathology in postmortem cortical tissue

Abstract

Psychiatric stress has been associated with accelerated epigenetic aging (i.e., when estimates of cellular age based on DNA methylation exceed chronological age) in both blood and brain tissue. Little is known about the downstream biological effects of accelerated epigenetic age on gene expression. In this study we examined associations between DNA methylation-derived estimates of cellular age that range from decelerated to accelerated relative to chronological age (“DNAm age residuals”) and transcriptome-wide gene expression. This was examined using tissue from three post-mortem cortical regions (ventromedial and dorsolateral prefrontal cortex and motor cortex, n = 97) from the VA National PTSD Brain Bank. In addition, we examined how posttraumatic stress disorder (PTSD) and alcohol-use disorders (AUD) moderated the association between DNAm age residuals and gene expression. Transcriptome-wide results across brain regions, psychiatric diagnoses, and cohorts (full sample and male and female subsets) revealed experiment-wide differential expression of 11 genes in association with PTSD or AUD in interaction with DNAm age residuals. This included the inflammation-related genes IL1B , RCOR2 , and GCNT1 . Candidate gene class analyses and gene network enrichment analyses further supported differential expression of inflammation/immune gene networks as well as glucocorticoid, circadian, and oxidative stress-related genes. Gene co-expression network modules suggested enrichment of myelination related processes and oligodendrocyte enrichment in association with DNAm age residuals in the presence of psychopathology. Collectively, results suggest that psychiatric stress accentuates the association between advanced epigenetic age and expression of inflammation genes in the brain. This highlights the role of inflammatory processes in the pathophysiology of accelerated cellular aging and suggests that inflammatory pathways may link accelerated cellular aging to premature disease onset and neurodegeneration, particularly in stressed populations. This suggests that anti-inflammatory interventions may be an important direction to pursue in evaluating ways to prevent or delay cellular aging and increase resilience to diseases of aging.

Sex-specific transcriptomic and epitranscriptomic signatures of PTSD-like fear acquisition

“…We observed a significant decrease in expression for only a single gene, Rps27A ; however, this was not validated using qPCR. There remains debate as to whether the amygdala is a sexually dimorphic structure ( Marwha et al., 2017 ; Wolf et al., 2021 ; Chatzinakos et al., 2021 ; Montalvo-Ortiz et al., 2022 ). Evidence suggests there are intrinsic differences linked to sex hormones that may explain our sex-specific observations in the formation and expression of emotional memories ( Blume et al., 2017 ; Morris et al., 2008 ; Cooke and Woolley, 2005 ).…”

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

“…We also estimated DNAm age using two recently developed tissue‐specific algorithms that were developed for human brain (Choi et al, 2019) and human cortical tissue (Shireby et al, 2020). Details of DNA extraction, QC procedures, genotype and DNAm data cleaning and imputation, ancestry assignment and ancestral principal component (PC) estimation, DNAm cell type estimates, and DNAm age (Horvath DNAm age, Choi brain‐specific DNAm age, and Shireby cortical DNAm age) calculation are reviewed in the Supporting Information Materials and were previously described (Logue et al, 2021; Morrison, Miller, et al, 2019; Wolf et al, 2021).…”

“…The primary aim of this study was to examine associations between PTSD, MDD, and AUD and age‐adjusted transcriptomic age in three brain regions using data from the VA National PTSD Brain Bank (Friedman et al, 2017). We have previously studied this same cohort to test associations between psychopathology and advanced DNAm age (Wolf et al, 2021) and to evaluate the gene expression correlates of advanced DNAm age (Wolf et al, 2021). A second aim was to identify the genes and related biological processes that drive associations between PTSD, MDD, and/or AUD and age‐adjusted transcriptomic age and to evaluate associations between age‐adjusted transcriptomic age and estimates of specific neural cell type counts.…”

Biomarkers of neurodegeneration in post-traumatic stress disorder: an integrative review

“…These mutations appeared to be linked to cytoskeletal and inflammation-related genes [48]. Finally, a post-mortem study of gene expression in the brains of veterans found four genes (SNORA73B, COL6A3, GCNT1 and GPRIN3) whose expression was associated with a lifetime diagnosis of PTSD [49].…”