Epigenetic and immune function profiles associated with posttraumatic stress disorder

Abstract

The biologic underpinnings of posttraumatic stress disorder (PTSD) have not been fully elucidated. Previous work suggests that alterations in the immune system are characteristic of the disorder. Identifying the biologic mechanisms by which such alterations occur could provide fundamental insights into the etiology and treatment of PTSD. Here we identify specific epigenetic profiles underlying immune system changes associated with PTSD. Using blood samples (n = 100) obtained from an ongoing, prospective epidemiologic study in Detroit, the Detroit Neighborhood Health Study, we applied methylation microarrays to assay CpG sites from more than 14,000 genes among 23 PTSD-affected and 77 PTSD-unaffected individuals. We show that immune system functions are significantly overrepresented among the annotations associated with genes uniquely unmethylated among those with PTSD. We further demonstrate that genes whose methylation levels are significantly and negatively correlated with traumatic burden show a similar strong signal of immune function among the PTSD affected. The observed epigenetic variability in immune function by PTSD is corroborated using an independent biologic marker of immune response to infection, CMV-a typically latent herpesvirus whose activity was significantly higher among those with PTSD. This report of peripheral epigenomic and CMV profiles associated with mental illness suggests a biologic model of PTSD etiology in which an externally experienced traumatic event induces downstream alterations in immune function by reducing methylation levels of immune-related genes.

Fig. 1.

Number of methylated and umethylated genes according to PTSD status. Red indicates the genes uniquely methylated or unmethylated in the PTSD-affected group, blue indicates the genes uniquely methylated or unmethylated in the PTSD-unaffected group, and green indicates the genes commonly methylated or unmethylated in both groups. Methylated genes were defined as those genes with average β values of >0.8, and unmethylated genes were defined as those genes with average β values of <0.2.

Fig. 2.

Sample FAC heat maps in the PTSD-affected group. Shown are the genes and associated annotations for FAC cluster 3 (A) and 2 (B) determined from the uniquely unmethylated and methylated gene sets, respectively.

Fig. 3.

Optical density ratios of CMV antibody levels among PTSD-affected and -unaffected individuals. Levels were significantly higher in the PTSD-affected group (Welch's t statistic = 2.48, 37 df, P = 0.016).