Gene expression in the dorsolateral and ventromedial prefrontal cortices implicates immune-related gene networks in PTSD

Abstract

Studies evaluating neuroimaging, genetically predicted gene expression, and pre-clinical genetic models of PTSD, have identified PTSD-related abnormalities in the prefrontal cortex (PFC) of the brain, particularly in dorsolateral and ventromedial PFC (dlPFC and vmPFC). In this study, RNA sequencing was used to examine gene expression in the dlPFC and vmPFC using tissue from the VA National PTSD Brain Bank in donors with histories of PTSD with or without depression (dlPFC n = 38, vmPFC n = 35), depression cases without PTSD (n = 32), and psychopathology-free controls (dlPFC n = 24, vmPFC n = 20). Analyses compared PTSD cases to controls. Follow-up analyses contrasted depression cases to controls. Twenty-one genes were differentially expressed in PTSD after strict multiple testing correction. PTSD-associated genes with roles in learning and memory (FOS, NR4A1), immune regulation (CFH, KPNA1) and myelination (MBP, MOBP, ERMN) were identified. PTSD-associated genes partially overlapped depression-associated genes. Co-expression network analyses identified PTSD-associated networks enriched for immune-related genes across the two brain regions. However, the immune-related genes and association patterns were distinct. The immune gene IL1B was significantly associated with PTSD in candidate-gene analysis and was an upstream regulator of PTSD-associated genes in both regions. There was evidence of replication of dlPFC associations in an independent cohort from a recent study, and a strong correlation between the dlPFC PTSD effect sizes for significant genes in the two studies (r = 0.66, p < 2.2 × 10^-16). In conclusion, this study identified several novel PTSD-associated genes and brain region specific PTSD-associated immune-related networks.

Keywords: Expression; PTSD; RNAseq; dlPFC; vmPFC.

Fig. 1

Volcano plot of PTSD-associated gene expression. Nominally significant (p < 0.05) genes are in green, and corrected significant genes are in red. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 2

Boxplots of the rlog normalized expression for PTSD cases and controls for the five most significant PTSD-associated genes.

Fig. 3

Effect sizes for PTSD and Depression for A) the five most significant PTSD-associated genes; B) candidate genes significant at the candidate-gene adjusted level (p_{cor-candidate}<0.05); and C). Gene networks significantly associated with PTSD.

Fig. 4

Venn diagrams of the overlap of nominally significant (p < 0.05) PTSD-associated genes A) across brain regions and sex and B) Across PTSD and depression. Note: p-values are based on permutation test with 1000 replicates.

Fig. 5

Comparing logfc from our dlPFC analyses to A) those presented in Girgenti et al. (2021). and B) the UPMC subset of that study which is independent of our cohort. Genes that are nominally significant (p < 0.05) in both studies are in red. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)