Posttraumatic Stress Disorder: An Immunological Disorder?

Wang, Zhewu; Caughron, Blaine; Young, Matthew R.

doi:10.3389/fpsyt.2017.00222

Cited by 63 publications

(59 citation statements)

References 85 publications

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“…41,42 Finally, the HLA-B complex may be related through the known role of immunity and inflammation in stress-related disorders. 43,44 Extensive follow-up work is needed to determine the function of identified genes and their relationship to putative pathological processes. For example, in SCZ the MHC locus is now thought to influence risk through pruning of synapses using immune machinery rather than through classical immune pathways.…”

Section: Discussionmentioning

confidence: 99%

Largest genome-wide association study for PTSD identifies genetic risk loci in European and African ancestries and implicates novel biological pathways

Nievergelt

Klengel

et al. 2018

Preprint

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Post-traumatic stress disorder (PTSD) is a common and debilitating disorder. The risk of PTSD following trauma is heritable, but robust common variants have yet to be identified by genome-wide association studies (GWAS). We have collected a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls. We first demonstrate significant genetic correlations across 60 PTSD cohorts to evaluate the comparability of these phenotypically heterogeneous studies. In this largest GWAS meta-analysis of PTSD to date we identify a total of 6 genome-wide significant loci, 4 in European and 2 in African-ancestry analyses. Follow-up analyses incorporated local ancestry and sex-specific effects, and functional studies. Along with other novel genes, a non-coding RNA (ncRNA) and a Parkinson's Disease gene, PARK2, were associated with PTSD. Consistent with previous reports, SNP-based heritability estimates for PTSD range between 10-20%. Despite a significant shared liability between PTSD and major depressive disorder, we show evidence that some of our loci may be specific to PTSD. These results demonstrate the role of genetic variation contributing to the biology of differential risk for PTSD and the necessity of expanding GWAS beyond European ancestry.Comparability of PGC2 studies PGC2 compiled the largest collection of global PTSD GWAS to date, with subjects recruited from both clinically deeply characterized, small patient groups and large cohorts with self-reported PTSD symptoms. We did not restrict the type of trauma subjects were exposed to, and trauma included both civilian and/or military events, often with pre-existing exposure to childhood trauma. To evaluate the comparability of these phenotypically heterogeneous studies we first estimated genetic correlations with LDSC, 15 a method that leverages GWAS summary results, the only data type available to PGC-PTSD for several of the larger military and non-US cohorts. We found significant genetic correlations (r g ) between studies using a cross-validation approach including all PGC2 EUA subjects (10 runs with studies randomly placed into 2 groups; mean r g = 0.56, mean SE = 0.23, mean p = 0.029, Supplementary Table 8).Next, additional analyses on the UK Biobank cohort (UKBB) were performed. This cohort comprises a very large proportion of the data, with almost as many EUA cases as the rest of the EUA PGC2 combined (referred to as PGC1.5). PTSD screening in UKBB was based on self-reported symptoms from a mental health survey. 16 We found a considerable genetic correlation between the UKBB and PGC1.5 EUA subjects (r g = 0.73, SE = 0.21, p = 0.0005; Supplementary Table 9). Further, sensitivity analyses in the UKBB using 3 alternative inclusion criteria for PTSD cases and controls showed stable correlations with PGC1.5 (P1 -P3; r g = 0.72 -0.79; Supplementary Table 10). Subsequent analyses were based on the UKBB phenotype including the largest number of subjects (P1; N = 126,188). Sex-stratified genetic correlations support the findings of a significant genetic signal...

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Section: Discussionmentioning

confidence: 99%

Largest genome-wide association study for PTSD identifies genetic risk loci in European and African ancestries and implicates novel biological pathways

Nievergelt

Klengel

et al. 2018

Preprint

Self Cite

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“…9 The prevalence of lifetime PTSD in the general US population is estimated to be between 6.1% and 8.3%. 12 Several studies have identified PTSD as a risk factor for cardiometabolic diseases as well as a predictor of poor outcomes in comorbid conditions such as acute myocardial infarction, asthma, and cancer. 12 Several studies have identified PTSD as a risk factor for cardiometabolic diseases as well as a predictor of poor outcomes in comorbid conditions such as acute myocardial infarction, asthma, and cancer.…”

Section: Introductionmentioning

confidence: 99%

“…10,11 PTSD has been postulated to be associated with modification of stress response in the body as well as causing a pro-inflammatory state. 12 Several studies have identified PTSD as a risk factor for cardiometabolic diseases as well as a predictor of poor outcomes in comorbid conditions such as acute myocardial infarction, asthma, and cancer. [13][14][15][16][17] PTSD has also been shown to be associated with other psychiatric comorbidities (depression, anxiety), substance abuse, and noncompliance with medications and follow-up.…”

Section: Introductionmentioning

confidence: 99%

History of posttraumatic stress disorder and outcomes after kidney transplantation

Siwakoti

Potukuchi

Thomas

et al. 2019

American Journal of Transplantation

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A history of posttraumatic stress disorder (PTSD), if uncontrolled, represents a contraindication for kidney transplantation. However, no previous large study has assessed the association between pretransplant history of PTSD and posttransplantation outcomes. We examined 4479 US veterans who had undergone transplantation. The diagnosis of history of PTSD was based on a validated algorithm. Measured covariates were used to create a matched cohort (n = 560). Associations between pretransplant PTSD and death with functioning graft, all-cause death, and graft loss were examined in survival models. Posttransplant medication nonadherence was assessed using proportion of days covered (PDC). From among 4479 veterans, 282 (6.3%) had a history of PTSD. The mean age ± standard deviation (SD) of the cohort at baseline was 61 ± 11 years, 91% were male, and 66% and 28% of patients were white and African American, respectively. Compared to patients without a history of PTSD, patients with a history of PTSD had a similar risk of death with a functioning graft (subhazard ratio [SHR] 0.97, 95% confidence interval [CI] 0.61-1.54), all-cause death (1.05, 0.69-1.58), and graft loss (1.09, 0.53-2.26). Moreover, there was no difference in | 2295 SIWAKOTI eT Al.

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“…Contrary to other psychiatric disorders that exhibit increased plasma levels of both cortisol and pro-inflammatory cytokines suggesting possible glucocorticoid (GC) resistance, PTSD is associated with enhanced GR sensitivity and inflammation (Hoge et al, 2009;Neigh and Ali, 2016;Wang et al, 2017). Although GC are well known for their anti-inflammatory properties, there are also accounts of the pro-inflammatory effects of GCs (Cruz-Topete and Cidlowski, 2015;Desmet and De Bosscher, 2017), where low dose glucocorticoids are associated with enhanced inflammatory responses and high doses are anti-inflammatory.…”

Section: Introductionmentioning

confidence: 99%

Role of enhanced glucocorticoid receptor sensitivity in inflammation in PTSD: Insights from a computational model for circadian-neuroendocrine-immune interactions

Somvanshi

Mellon²,

Yehuda

et al. 2019

Preprint

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AbstractAlthough glucocorticoid resistance contributes to increased inflammation, individuals with post-traumatic stress disorder (PTSD) exhibit increased glucocorticoid receptor (GR) sensitivity along with increased inflammation. It is not clear how inflammation co-exists with a hyper-responsive hypothalamic pituitary adrenal axis (HPA axis). To understand this better, we developed and analyzed an integrated mathematical model for the HPA axis and the immune system. We performed mathematical simulations for a dexamethasone suppression test and IC50-dexamethasone for cytokine suppression, by varying model parameters. The model analysis suggests that increasing the steepness of the dose response curve for GR activity may reduce anti-inflammatory effects of GRs at the ambient glucocorticoid levels thereby increasing pro-inflammatory response. The adaptive response of pro-inflammatory cytokine mediated stimulatory effects on the HPA-axis is reduced due to dominance of the GR-mediated negative feedback on the HPA-axis. To verify these hypotheses we analyzed the clinical data on neuro-endocrine variables and cytokines obtained from war-zone veterans with and without PTSD. We observed significant group differences for cortisol and ACTH suppression tests, pro-inflammatory cytokines TNFα and IL6, hs-CRP, promoter methylation of GR gene and IC50-Dex for lysozyme suppression. Causal inference modelling revealed significant associations between cortisol suppression and post-dex cortisol decline, promoter methylation of NR3C1-1F, IC50-Dex and pro-inflammatory cytokines. We noted significant mediation effects of NR3C1-1F promoter methylation on inflammatory cytokines through changes in GR sensitivity. Our findings suggest that increased GR sensitivity may contribute to increased inflammation, therefore, interventions to restore GR sensitivity may normalize inflammation in PTSD.

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Posttraumatic Stress Disorder: An Immunological Disorder?

Cited by 63 publications

References 85 publications

Largest genome-wide association study for PTSD identifies genetic risk loci in European and African ancestries and implicates novel biological pathways

Largest genome-wide association study for PTSD identifies genetic risk loci in European and African ancestries and implicates novel biological pathways

History of posttraumatic stress disorder and outcomes after kidney transplantation

Role of enhanced glucocorticoid receptor sensitivity in inflammation in PTSD: Insights from a computational model for circadian-neuroendocrine-immune interactions

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