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Methylomic profiles reveal sex-specific differences in leukocyte composition associated with post-traumatic stress disorder.

ABSTRACT: Post-traumatic stress disorder (PTSD) is a debilitating mental disorder precipitated by trauma exposure. However, only some persons exposed to trauma develop PTSD. There are sex differences in risk; twice as many women as men develop a lifetime diagnosis of PTSD. Methylomic profiles derived from peripheral blood are well-suited for investigating PTSD because DNA methylation (DNAm) encodes individual response to trauma and may play a key role in the immune dysregulation characteristic of PTSD pathophysiology. In the current study, we leveraged recent methodological advances to investigate sex-specific differences in DNAm-based leukocyte composition that are associated with lifetime PTSD. We estimated leukocyte composition on a combined methylation array dataset (483 participants, ∼450 k CpG sites) consisting of two civilian cohorts, the Detroit Neighborhood Health Study and Grady Trauma Project. Sex-stratified Mann-Whitney U test and two-way ANCOVA revealed that lifetime PTSD was associated with significantly higher monocyte proportions in males, but not in females (Holm-adjusted p-val < 0.05). No difference in monocyte proportions was observed between current and remitted PTSD cases in males, suggesting that this sex-specific difference may reflect a long-standing trait of lifetime history of PTSD, rather than current state of PTSD. Associations with lifetime PTSD or PTSD status were not observed in any other leukocyte subtype and our finding in monocytes was confirmed using cell estimates based on a different deconvolution algorithm, suggesting that our sex-specific findings are robust across cell estimation approaches. Overall, our main finding of elevated monocyte proportions in males, but not in females with lifetime history of PTSD provides evidence for a sex-specific difference in peripheral blood leukocyte composition that is detectable in methylomic profiles and that may reflect long-standing changes associated with PTSD diagnosis.

SUBMITTER: Kim GS

PROVIDER: S-EPMC6754791 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Methylomic profiles reveal sex-specific differences in leukocyte composition associated with post-traumatic stress disorder.

Kim Grace S GS Smith Alicia K AK Xue Fei F Michopoulos Vasiliki V Lori Adriana A Armstrong Don L DL Aiello Allison E AE Koenen Karestan C KC Galea Sandro S Wildman Derek E DE Uddin Monica M

Brain, behavior, and immunity 20190619

Post-traumatic stress disorder (PTSD) is a debilitating mental disorder precipitated by trauma exposure. However, only some persons exposed to trauma develop PTSD. There are sex differences in risk; twice as many women as men develop a lifetime diagnosis of PTSD. Methylomic profiles derived from peripheral blood are well-suited for investigating PTSD because DNA methylation (DNAm) encodes individual response to trauma and may play a key role in the immune dysregulation characteristic of PTSD pat ...[more]

PMID: 31228611

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Project description:The biological underpinnings of post-traumatic stress disorder (PTSD) have not been fully elucidated. Previous work suggests that alterations in the immune system are characteristic of the disorder. Identifying the biological 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 (DNHS), we applied methylation microarrays to assay CpG sites from over 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 biological marker of immune response to infection, cytomegalovirus—a typically latent herpesvirus whose activity was significantly higher among those with PTSD. These results provide the first report of peripheral epigenomic and CMV profiles associated with mental illness and suggest a new biological 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. Bisulfite conversion of whole blood-derived DNA samples was performed using the EZ-96 DNA methylation kit from Zymo Research. One microgram (μg) of each sample (including controls) was subjected to bisulfite conversion following manufacturer’s recommended protocol. 100 samples were analyzed of which 23 are PTSD affected and 77 are PTSD-unaffected. There were four technical replicates comprised of duplicate samples of two randomly selected individuals from the n=100 and duplicate samples of the control human methylated and unmethylated DNA.

Project description:BackgroundSocial-stress mouse model, based on the resident-intruder paradigm was used to simulate features of human post-traumatic stress disorder (PTSD). The model involved exposure of an intruder (subject) mouse to a resident aggressor mouse followed by exposure to trauma reminders with rest periods. C57BL/6 mice exposed to SJL aggressor mice exhibited behaviors suggested as PTSD-in-mouse phenotypes: intermittent freezing, reduced locomotion, avoidance of the aggressor-associated cue and apparent startled jumping. Brain tissues (amygdala, hippocampus, medial prefrontal cortex, septal region, corpus striatum and ventral striatum) from subject (aggressor exposed: Agg-E) and control C57BL/6 mice were collected at one, 10 and 42 days post aggressor exposure sessions. Transcripts in these brain regions were assayed using Agilent's mouse genome-wide arrays.ResultsPathways and biological processes associated with differentially regulated genes were mainly those thought to be involved in fear-related behavioral responses and neuronal signaling. Expression-based assessments of activation patterns showed increased activations of pathways related to anxiety disorders (hyperactivity and fear responses), impaired cognition, mood disorders, circadian rhythm disruption, and impaired territorial and aggressive behaviors. In amygdala, activations of these pathways were more pronounced at earlier time-points, with some attenuation after longer rest periods. In hippocampus and medial prefrontal cortex, activation patterns were observed at later time points. Signaling pathways associated with PTSD-comorbid conditions, such as diabetes, metabolic disorder, inflammation and cardiac infarction, were also significantly enriched. In contrast, signaling processes related to neurogenesis and synaptic plasticity were inhibited.ConclusionsOur data suggests activations of behavioral responses associated with anxiety disorders as well as inhibition of neuronal signaling pathways important for neurogenesis, cognition and extinction of fear memory. These pathways along with comorbid-related signaling pathways indicate the pervasive and multisystem effects of aggressor exposure in mice, potentially mirroring the pathologic conditions of PTSD patients.

Project description:The long-term effects of mild TBI (mTBI) are not well understood, and there is an ongoing debate about whether there are sex differences in outcomes following mTBI. This study examined i) symptom burden and functional outcomes at 8-years post-injury in males and females following mTBI; ii) sex differences in outcomes at 8-years post-injury for those aged <45 years and ≥45 years and; iii) sex differences in outcomes for single and repetitive TBI. Adults (≥16 years at injury) identified as part of a population-based TBI incidence study (BIONIC) who experienced mTBI 8-years ago (N = 151) and a TBI-free sample (N = 151) completed self-report measures of symptoms and symptom burden (Rivermead Post-Concussion Symptom Questionnaire, Hospital Anxiety and Depression Scale, Post-traumatic Stress Disorder Checklist), and functional outcomes (Participation Assessments with Recombined Tools, Work Limitations Questionnaire). The mTBI group reported significantly greater post-concussion symptoms compared to the TBI-free group (F(1,298) = 26.84, p<.01, ηp2 = .08). Females with mTBI were twice as likely to exceed clinical cut-offs for post-concussive (X2 (1)>5.2, p<.05, V>.19) and PTSD symptoms (X2(1) = 6.10, p = .014, V = .20) compared to the other groups, and reported their health had the greatest impact on time-related work demands (F(1,171) = 4.36, p = .04, ηp2 = .03. There was no interaction between sex and age on outcomes. The repetitive mTBI group reported significantly greater post-concussion symptoms (F(1,147) = 9.80, p<.01, ηp2 = .06) compared to the single mTBI group. Twice the proportion of women with repetitive mTBI exceeded the clinical cut-offs for post-concussive (X2(1)>6.90, p<.01, V>.30), anxiety (X2(1)>3.95, p<.05, V>.23) and PTSD symptoms (X2(1)>5.11, p<.02, V>.26) compared with males with repetitive TBI or women with single TBI. Thus, at 8-years post-mTBI, people continued to report a high symptom burden. Women with mTBI, particularly those with a history of repetitive mTBI, had the greatest symptom burden and were most likely to have symptoms of clinical significance. When treating mTBI it is important to assess TBI history, particularly in women. This may help identify those at greatest risk of poor long-term outcomes to direct early treatment and intervention.

Project description:There is a well-known association of traumatic experiences and posttraumatic stress disorder (PTSD) with body size and composition, including consistent differences between sexes. However, the biology underlying these associations is unclear. To understand the genetic underpinnings of this complex relationship, we investigated genome-wide datasets informative of African and European ancestries from the Psychiatric Genomic Consortium, the UK Biobank, the GIANT Consortium, and the Million Veteran Program. We used genome-wide association statistics to estimate sex-specific genetic correlations (r g ) of traumatic experiences, social support, and PTSD with multiple anthropometric traits. After multiple testing corrections (false discovery rate, FDR q < 0.05), we observed 58 significant r g relationships in females (e.g., childhood physical abuse and body mass index, BMI r g = 0.245, p = 3.88 × 10-10) and 21 significant r g relationships in males (e.g., been involved in combat or exposed to warzone and leg fat percentage; r g = 0.405, p = 4.42 × 10-10). We performed causal inference analyses of these genetic overlaps using Mendelian randomization and latent causal variable approaches. Multiple female-specific putative causal relationships were observed linking body composition/size with PTSD (e.g., leg fat percentage→PTSD; beta = 0.319, p = 3.13 × 10-9), traumatic experiences (e.g., childhood physical abuse→waist circumference; beta = 0.055, p = 5.07 × 10-4), and childhood neglect (e.g., "someone to take you to doctor when needed as a child"→BMI; beta = -0.594, p = 1.09 × 10-5). In males, we observed putative causal effects linking anthropometric-trait genetic liabilities to traumatic experiences (e.g., BMI→childhood physical abuse; beta = 0.028, p = 8.19 × 10-3). Some of these findings were replicated in individuals of African descent although the limited sample size available did not permit us to conduct a sex-stratified analysis in this ancestry group. In conclusion, our findings provide insights regarding sex-specific causal networks linking anthropometric traits to PTSD, traumatic experiences, and social support.

Dataset Information

Methylomic profiles reveal sex-specific differences in leukocyte composition associated with post-traumatic stress disorder.

Publications

Methylomic profiles reveal sex-specific differences in leukocyte composition associated with post-traumatic stress disorder.

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