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.epidemiology | methylation | cytomegalovirus | cumulative trauma | psychiatry

BackgroundRecent work suggests that epigenetic differences may be associated with psychiatric disorders. Here we investigate, in a community-based sample, whether methylation profiles distinguish between individuals with and without lifetime depression. We also investigate the physiologic consequences that may be associated with these profiles.MethodUsing whole blood-derived genomic DNA from a subset of participants in the Detroit Neighborhood Health Study (DNHS), we applied methylation microarrays to assess genome-wide methylation profiles for over 14 000 genes in 33 persons who reported a lifetime history of depression and 67 non-depressed adults. Bioinformatic functional analyses were performed on the genes uniquely methylated and unmethylated in each group, and inflammatory biomarkers [interleukin (IL)-6 and C-reactive protein (CRP)] were measured to investigate the possible functional significance of the methylation profiles observed.ResultsUniquely unmethylated gene sets distinguished between those with versus without lifetime depression. In particular, some processes (e.g. brain development, tryptophan metabolism) showed patterns suggestive of increased methylation among individuals with depression whereas others (e.g. lipoprotein) showed patterns suggestive of decreased methylation among individuals with depression. IL-6 and CRP levels were elevated among those with lifetime depression and, among those with depression only, IL-6 methylation showed an inverse correlation with circulating IL-6 and CRP.ConclusionsGenome-wide methylation profiles distinguish individuals with versus without lifetime depression in a community-based setting, and show coordinated signals with pathophysiological mechanisms previously implicated in the etiology of this disorder. Examining epigenetic mechanisms in concert with other dynamic markers of physiologic functioning should improve our understanding of the neurobiology of depression.

Abstract. As potential regulators of DNA accessibility and activity, epigenetic modifications offer a mechanism by which the environment can moderate the effects of genes. To date, however, there have been relatively few studies assessing epigenetic modifications associated with post-traumatic stress disorder (PTSD). Here we investigate PTSD-associated methylation differences in 33 genes previously shown to differ in whole blood-derived gene expression levels between those with vs. without the disorder. Drawing on DNA samples similarly obtained from whole blood in 100 individuals, 23 with and 77 without lifetime PTSD, we used methylation microarray data to assess whether these 33 candidate genes showed epigenetic signatures indicative of increased risk for, or resilience to, PTSD. Logistic regression analyses were performed to assess the main and interacting effects of candidate genes' methylation values and number of potentially traumatic events (PTEs), adjusting for age and other covariates. Results revealed that only one candidate gene -MAN2C1 -showed a significant methylation x PTE interaction, such that those with both higher MAN2C1 methylation and greater exposure to PTEs showed a marked increase in risk of lifetime PTSD (OR 4.35, 95% CI: 1.07, 17.77, p = 0.04). These results indicate that MAN2C1 methylation levels modify cumulative traumatic burden on risk of PTSD, and suggest that both gene expression and epigenetic changes at specific loci are associated with this disorder.

Objective-The well-documented gender differences in the risk for depression may be explained by genetic factors, by different responses to social context, or by a combination of both. We sought to assess whether there were gender differences in the longitudinal associations between serotonin transporter promoter (5-HTTLPR) genotype and depressive symptoms in adolescents, and whether macrosocial context plays a role in explaining any observed differences.Methods-Using data from a nationally representative survey of adolescents, we applied multilevel mixed models to assess, separately for adolescent males and females (a) the relation between 5-HTTLPR genotype and depressive symptoms; and (b) the interaction of county-level deprivation and 5-HTTLPR genotype in models predicting depressive symptoms. All models adjusted for age and other covariates.Results-Among females (n=560), main effects models showed an association between the sl genotype and lowered risk of depressive symptoms (b=−0.18, p=0.03). Among males (n=524), interaction models showed an association between sl genotype and lowered risk of depressive symptoms in deprived counties only (b=−0.32, p=0.04).Conclusions-In adolescent females, the 5-HTTLPR sl genotype confers protection against depressive symptoms independent of county-level social context whereas in adolescent males, protection by the same genotype is conferred only within the context of county-level deprivation. Future work should aim to understand how genetic and macrosocial factors jointly shape risk for mental illness, and how these factors shape gender differences in mental illness.

Objective The well-documented gender differences in the risk for depression may be explained by genetic factors, by different responses to social context, or by a combination of both. We sought to assess whether there were gender differences in the longitudinal associations between serotonin transporter promoter (5-HTTLPR) genotype and depressive symptoms in adolescents, and whether macrosocial context plays a role in explaining any observed differences. Methods Using data from a nationally representative survey of adolescents, we applied multilevel mixed models to assess, separately for adolescent males and females (a) the relation between 5-HTTLPR genotype and depressive symptoms; and (b) the interaction of county-level deprivation and 5-HTTLPR genotype in models predicting depressive symptoms. All models adjusted for age and other covariates. Results Among females (n=560), main effects models showed an association between the sl genotype and lowered risk of depressive symptoms (b=−0.18, p=0.03). Among males (n=524), interaction models showed an association between sl genotype and lowered risk of depressive symptoms in deprived counties only (b=−0.32, p=0.04). Conclusions In adolescent females, the 5-HTTLPR sl genotype confers protection against depressive symptoms independent of county-level social context whereas in adolescent males, protection by the same genotype is conferred only within the context of county-level deprivation. Future work should aim to understand how genetic and macrosocial factors jointly shape risk for mental illness, and how these factors shape gender differences in mental illness.