Gene Expression Patterns Associated with Posttraumatic Stress Disorder Following Exposure to the World Trade Center Attacks

Yehuda, Rachel; Cai, Guiqing; Golier, Julia A.; Sarapas, Casey; Galea, Sandro; Ising, Marcus; Rein, Theo; Schmeidler, James; Müller‐Myhsok, Bertram; Holsboer, Florian; Buxbaum, Joseph D.

doi:10.1016/j.biopsych.2009.02.034

Cited by 267 publications

(175 citation statements)

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“…Among the 33 loci identified as showing differential gene expression in whole blood between those with vs. without PTSD [18,19], only one demonstrated a significant (p = 0.04) methylation x PTE interaction on risk of PTSD: mannosidase, alpha, class 2C, member 1(MAN2C1), which showed this effect at CpG site cg04008455 on the HM27 BeadChip. Table 2 presents the descriptive statistics and bivariate associations for the whole sample and for those with vs. without lifetime PTSD for the variables included in our final MAN2C1 model.…”

Section: Resultsmentioning

confidence: 99%

“…We assembled a list of the genes (n = 33; Table 1) identified as significantly differentially expressed between those with vs. without PTSD in whole blood based on two previous studies [18,19]. Genes were included in the list if they showed PTSD-associated differences in gene expression in either of the two studies [18,19] and were also represented on the HM27 BeadChip.…”

Section: Analysesmentioning

confidence: 99%

“…Genes were included in the list if they showed PTSD-associated differences in gene expression in either of the two studies [18,19] and were also represented on the HM27 BeadChip. We then tested for potential main and interaction effects between methylation at CpG sites associated with these 33 loci and number of potentially traumatic events on risk of PTSD.…”

Section: Analysesmentioning

confidence: 99%

“…The majority of downregulated transcripts (which were the focus of the study) were associated with immune functions or with reactive oxygen species. Most recently, Yehuda and colleagues reported whole blood-derived gene expression levels among PTSD-affected and -unaffected individuals who had had exposure to the 9/11 attack on New York City [19]. Differential expression was detected in 16 distinct genes, several of which are involved in signal transduction, brain and immune cell function and HPA axis activity.…”

Section: Introductionmentioning

confidence: 99%

“…The goal of this work was to conduct a secondary data analysis of the extant PTSD-associated genomic data in order to build a platform for future studies that assess both gene expression and epigenetic differences associated with PTSD from the same individuals, in the same tissues. Since epigenetic variation occurs in a tissue-specific fashion [23], we focused on the two studies that assessed gene expression in peripheral whole blood [18,19], consistent with the starting material of PTSD-associated epigenetic signatures reported in a previous recent study [16]. Furthermore, we focused our analyses on the potential interaction between methylation values of these candidate genes and cumulative traumatic burden, in order to investigate more fully the complex ways in which internal (molecular) and external (PTE) factors may modify risk for this mental illness and result in phenotypic variation following trauma exposure [24].…”

Section: Introductionmentioning

confidence: 99%

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Gene Expression and Methylation Signatures ofMAN2C1are Associated with PTSD

et al. 2011

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Analysesmentioning

confidence: 99%

Section: Analysesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Gene Expression and Methylation Signatures ofMAN2C1are Associated with PTSD

et al. 2011

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Using Polymorphisms in FKBP5 to Define Biologically Distinct Subtypes of Posttraumatic Stress Disorder

Mehta

Gonik²,

Klengel

et al. 2011

Arch Gen Psychiatry

186

123

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Context Polymorphisms in the gene encoding the glucocorticoid receptor (GR) regulating co-chaperone FKBP5 have been shown to alter GR sensitivity and are associated with an increased risk to develop posttraumatic stress disorder (PTSD). Objective To investigate interactions of the FKBP5 single-nucleotide polymorphism rs9296158 and PTSD symptoms on baseline cortisol level, low-dose dexamethasone suppression, and whole-blood gene expression. Design Association of FKBP5 genotypes and PTSD symptoms with endocrine measures and genome-wide expression profiles. Setting Waiting rooms of general medical and gynecological clinics of an urban hospital at Emory University. Participants The 211 participants were primarily African American (90.05%) and of low socioeconomic status and had high rates of trauma and PTSD. Main Outcome Measures Baseline and post–dexamethasone suppression cortisol measures and gene expression levels. Results In our endocrine study, we found that only risk allele A carriers of rs9296158 showed GR supersensitivity with PTSD; in contrast, baseline cortisol levels were decreased in PTSD only in patients with the GG genotype. Expression of 183 transcripts was significantly correlated with PTSD symptoms after multiple testing corrections. When adding FKBP5 genotype and its interaction with PTSD symptoms, expression levels of an additional 32 genes were significantly regulated by the interaction term. Within these 32 genes, previously reported PTSD candidates were identified, including FKBP5 and the IL18 and STAT pathways. Significant overrepresentation of steroid hormone transcription factor binding sites within these 32 transcripts was observed, highlighting the fact that the earlier-described genotype and PTSD-dependent differences in GR sensitivity could drive the observed gene expression pattern. Results were validated by reverse transcriptase–polymerase chain reaction and replicated in an independent sample (N=98). Conclusions These data suggest that the inheritance of GR sensitivity–moderating FKBP5 polymorphisms can determine specific types of hypothalamic-pituitary-adrenal axis dysfunction within PTSD, which are also reflected in gene-expression changes of a subset of GR-responsive genes. Thus, these findings indicate that functional variants in FKBP5 are associated with biologically distinct subtypes of PTSD.

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Early pharmacological interventions for preventing post-traumatic stress disorder (PTSD): a network meta-analysis

Bertolini

Robertson

Ostuzzi

et al. 2019

Cochrane Database of Systematic Reviews

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This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the efficacy and acceptability of pharmacological interventions for preventing post-traumatic stress disorder (PTSD) in adults exposed to a traumatic event and to generate a clinically useful ranking of pharmacological interventions according to their efficacy and acceptability by performing a network metaanalysis. B A C K G R O U N D Description of the condition Post-traumatic stress disorder (PTSD) is a severe and debilitating disorder which may develop in people exposed to traumatic events. Up to 80% of the adult population in the USA have been exposed to a traumatic event eligible for diagnosis of PTSD (Breslau 2012), and estimates are similar for Europe (de Vries 2009). The lifetime prevalence of PTSD is estimated at 6.8% (Kessler 2005), and the 12-month prevalence at 3.5% (Kessler 2005a). General prevalence rates are higher in displaced populations (Bogic 2015; Turrini 2017), and populations exposed to conflict (Steel 2009). According to the Diagnostic and Statistical Manual of Mental Disorders, FiJh Edition (DSM-5), traumatic events eligible for the diagnosis "include, but are not limited to, exposure to war as a combatant or civilian, threatened or actual physical assault, threatened or actual sexual violence, being kidnapped, being taken hostage, terrorist attack, torture, incarceration as a prisoner of war, natural or human-made disasters, and severe motor vehicle accidents" (APA 2013). As stated by the DSM, this list is not comprehensive and many different traumatic events have proved capable of triggering PTSD. For instance, in recent years there has been an increase in reports of PTSD in survivors of critical illness, with an estimated prevalence of 25% among this population (Wade 2013). With some limitations regarding the nature of the traumatic incident, witnessing a trauma, learning that a relative or close friend was exposed to trauma, or being exposed to aversive details about a trauma (as in the course of professional duties) may also precipitate PTSD (APA 2013). Not all individuals exposed to traumatic experiences will develop PTSD. The likelihood of developing PTSD is associated with a number of pre-, peri-, and post-traumatic factors (Bisson 2007; Qi 2016), such as history of a psychiatric disorder, gender (females are more vulnerable than males), low socioeconomic status, belonging to a minority, history of previous trauma, genetic endowment and epigenetic regulation, impaired executive functioning and higher emotional reactivity (Aupperle 2012; Guthrie 2005), the severity of the trauma itself, the perceived threat to life, whether the event was intentional or unintentional, peritraumatic emotions and dissociation (Ozer 2003), and the perceived lack of social support and subsequent life stress (e.g. inability to work as a result of the event) (Brewin 2000). Individuals who develop PTSD following a trauma may experience a wide range of symptoms, which are presented in four categories in the DSM-...

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Gene Expression Patterns Associated with Posttraumatic Stress Disorder Following Exposure to the World Trade Center Attacks

Abstract: Consistent with observations of HPA axis dysfunction in PTSD, several genes involved in glucocorticoid signaling are differentially expressed among those with current PTSD.

Cited by 267 publications

References 17 publications

Gene Expression and Methylation Signatures ofMAN2C1are Associated with PTSD

Gene Expression and Methylation Signatures ofMAN2C1are Associated with PTSD

Using Polymorphisms in FKBP5 to Define Biologically Distinct Subtypes of Posttraumatic Stress Disorder

Early pharmacological interventions for preventing post-traumatic stress disorder (PTSD): a network meta-analysis

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