The epigenetic changes are affected by sex and valproic acid treatment in a rat model of post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) presents distinct sex-specific differences in both symptom expression and treatment outcomes, with the underlying biological mechanisms still remain unclear. Epigenetic modifications, particularly histone acetylation, have been increasingly recognized as critical factors in the pathophysiology of PTSD. Valproic acid (VPA), a potent histone deacetylase (HDAC) inhibitor, has shown promise in modulating epigenetic responses and improving therapeutic outcomes is PTSD, though its effect may differ between sexes. This study aimed to explore the sex-specific epigenetic changes in response to trauma and the impact of VPA treatment in a rat model of PTSD induced by predator scent stress. Sprague-Dawley rats of both sexes were randomly assigned to stressed and non-stressed groups and treated with either VPA (100 mg/kg) or vehicle. Anxiety levels were assessed using the elevated plus maze, followed by analysis of histone H3 and H4 acetylation, HDAC activity, and c-fos expression in the hippocampus. Our findings revealed that traumatic stress led to increased freezing time and anxiety levels, with more pronounced effects observed in females. Additionally, we have identified sex-specific differences in hippocampal epigenetic modifications; stressed females exhibited higher H3 acetylation, and VPA-treated stressed males showed increased H4 acetylation. These results highlight the importance of considering sex differences in the epigenetic mechanism underlying PTSD and suggest that personalized therapeutic approaches may be necessary to address these complexities.

PTSD biomarkers: Neuroendocrine signaling to epigenetic variants.

Posttraumatic stress disorder (PTSD) is characterized by exposure to traumatic events and involves symptom domains such as intrusive thoughts, avoidant behaviors, negative mood, and cognitive dysfunction. The disorder can be chronic and debilitating, and the heterogenous nature and varied presentation of PTSD has afforded difficulty in determining efficacious treatment. The ability to identify biomarkers for PTSD risk, prognosis, or for the purposes of treatment, would be highly valuable. There is evidence for peripheral biomarkers related to the hypothalamic-pituitary-adrenal axis, the immune system, neurotransmitters and neurohormones, while genome and epigenome wide association studies have identified genes of interest relating to neurocircuitry, monoaminergic function, and the immune system. Importantly, however, reproducibility is a persistent issue. Considerations for future research include the need for well-powered and well-designed studies to determine directionality, in addition to considering biomarkers as they relate to symptom domains and the spectrum of symptom severity rather than dichotomous diagnostic outcomes. We conclude by recommending the staging of biological processes and PTSD symptoms, from subsyndromal to chronic, which could eventually facilitate selection of personalized treatment interventions for individuals with PTSD, in addition to serving as a future framework for biomarker data.

The shared genetic etiology of antisocial behavior and psychiatric disorders: Insights from pleiotropy and causality analysis.

BACKGROUND: Antisocial behavior (ASB) infringes on the rights of others and significantly disrupts social order. Studies have shown that ASB is phenotypically associated with various psychiatric disorders. However, these studies often neglected the importance of genetic foundations. METHODS: This study utilized genome-wide association studies and pleiotropy analysis to explore the genetic correlation between ASB and psychiatric disorders. Linkage disequilibrium score regression (LDSC) and high-definition likelihood (HDL) methods were employed to assess genetic correlations, and the PLACO method was used for pleiotropy analysis. Functional annotation and biological pathway analysis of identified pleiotropic genes were performed using enrichment analysis. Furthermore, Mendelian randomization (MR) analysis was conducted to validate these causal relationships. RESULTS: LDSC and HDL analysis showed that significant positive genetic correlations were between ASB and attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ), major depressive disorder (MDD), and post-traumatic stress disorder (PTSD). Multiple potential pleiotropic genetic loci were identified, particularly the FOXP2 and MDFIC genes located at the 7q31.1 locus. Enrichment analysis showed that these pleiotropic genes are highly expressed in several brain regions (such as the hypothalamus, cerebellar hemisphere, cortex, and amygdala) and immune-related cells. MR analysis further confirmed the causal effects ADHD, SCZ, and MDD on ASB risk. CONCLUSION: This study reveals significant genetic correlations and potential causal mechanisms between ASB and various psychiatric disorders. The MR analysis confirmed the causal effects of psychiatric disorders on ASB. These findings deepen our understanding of the genetic architecture of psychiatric disorders and ASB.

Subjective cognitive concerns, APOE ε4, PTSD symptoms, and risk for dementia among older veterans.

BACKGROUND: Posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) are associated with self-reported problems with cognition as well as risk for Alzheimer's disease and related dementias (ADRD). Overlapping symptom profiles observed in cognitive disorders, psychiatric disorders, and environmental exposures (e.g., head injury) can complicate the detection of early signs of ADRD. The interplay between PTSD, head injury, subjective (self-reported) cognitive concerns and genetic risk for ADRD is also not well understood, particularly in diverse ancestry groups. METHODS: Using data from the U.S. Department of Veterans Affairs (VA) Million Veteran Program (MVP), we examined the relationship between dementia risk factors (APOE ε4, PTSD, TBI) and subjective cognitive concerns (SCC) measured in individuals of European (n = 140,921), African (n = 15,788), and Hispanic (n = 8,064) ancestry (EA, AA, and HA, respectively). We then used data from the VA electronic medical record to perform a retrospective survival analysis evaluating PTSD, TBI, APOE ε4, and SCC and their associations with risk of conversion to ADRD in Veterans aged 65 and older. RESULTS: PTSD symptoms (B = 0.50-0.52, p < 1E-250) and probable TBI (B = 0.05-0.19, p = 1.51E-07 - 0.002) were positively associated with SCC across all three ancestry groups. APOE ε4 was associated with greater SCC in EA Veterans aged 65 and older (B = 0.037, p = 1.88E-12). Results of Cox models indicated that PTSD symptoms (hazard ratio [HR] = 1.13-1.21), APOE ε4 (HR = 1.73-2.05) and SCC (HR = 1.18-1.37) were positively associated with risk for ADRD across all three ancestry groups. In the EA group, probable TBI also contributed to increased risk of ADRD (HR = 1.18). CONCLUSIONS: The findings underscore the value of SCC as an indicator of ADRD risk in Veterans 65 and older when considered in conjunction with other influential genetic, clinical, and demographic risk factors.

Epigenetic Age Acceleration and Disparities in Posttraumatic Stress in Women in Southeast Louisiana: NIMHD Social Epigenomics Program.

Importance: Disasters experienced by an entire community provide opportunities to understand individual differences in risk for adverse health outcomes over time. DNA methylation (DNAm) differences may help to distinguish individuals at increased risk following large-scale disasters. Objective: To examine the association of epigenetic age acceleration with probable posttraumatic stress disorder (PTSD) and PTSD symptom severity in women. Design, Setting, and Participants: This prospective cohort study examined data from participants in the Women and Their Children's Health cohort, who were characterized longitudinally following the Deepwater Horizon oil spill (DHOS) in 2010 and through numerous hurricanes in the Gulf Coast region of the US. Wave 1 occurred August 6, 2012, through June 26, 2014, and wave 2 occurred September 2, 2014, through May 27, 2016. Data were analyzed between August 18 and November 4, 2023. Address-based sampling was used to recruit women aged 18 to 80 years and residing in 1 of the 7 Louisiana parishes surrounding the DHOS-affected region. Recruitment consisted of 2-stage sampling that (1) undersampled the 2 more urban parishes to maximize probability of participant oil exposure and (2) proportionally recruited participants across census tracts in the 5 other parishes closest to the spill. Exposure: Posttraumatic stress subsequent to the DHOS. Main Outcome and Measures: Epigenetic age acceleration was measured by DNAm assayed from survey wave 1 blood samples. Posttraumatic stress disorder was assessed using the PTSD Checklist for DSM-5 at survey wave 2, and lifetime trauma exposure was assessed using the Life Events Checklist for DSM-5. General linear models were used to examine the association between wave 1 DNAm age and wave 2 probable PTSD diagnosis and symptom severity. Results: A total of 864 women (mean [SD] age, 47.1 [12.0] years; 328 Black [38.0%], 19 American Indian [2.2%], 486 White [56.3%], and 30 of other racial groups, including uknown or unreported [3.5%]) were included. Black and American Indian participants had a higher age acceleration at wave 1 compared with White participants (ß = 1.64 [95% CI, 1.02-2.45] and 2.34 [95% CI, 0.33-4.34], respectively), and they had higher PTSD symptom severity at wave 2 (ß = 7.10 [95% CI, 4.62-9.58] and 13.08 [95% CI, 4.97-21.18], respectively). Epigenetic age acceleration at wave 1 was associated with PTSD symptom severity at wave 2 after adjusting for race, smoking, body mass index, and household income (ß = 0.38; 95% CI, 0.11-0.65). Conclusions and Relevance: In this cohort study, epigenetic age acceleration was higher in minoritized racial groups and associated with future PTSD diagnosis and severity. These findings support the need for psychoeducation about traumatic responses to increase the likelihood that treatment is sought before years of distress and entrenchment of symptoms and comorbidities occur.

Distinct saliva DNA methylation profiles in relation to treatment outcome in youth with posttraumatic stress disorder.

In youth with posttraumatic stress disorder (PTSD) non-response rates after treatment are often high. Epigenetic mechanisms such as DNA methylation (DNAm) have previously been linked to PTSD pathogenesis, additionally DNAm may affect response to (psychological) therapies. Besides investigating the direct link between DNAm and treatment response, it might be helpful to investigate the link between DNAm and previously associated biological mechanisms with treatment outcome. Thereby gaining a deeper molecular understanding of how psychotherapy (reflecting a change in the environment) relates to epigenetic changes and the adaptability of individuals. To date, limited research is done in clinical samples and no studies have been conducted in youth. Therefore we conducted a study in a Dutch cohort of youth with and without PTSD (n = 87, age 8-18 years). We examined the cross-sectional and longitudinal changes of saliva-based genome-wide DNA methylation (DNAm) levels, and salivary cortisol secretion. The last might reflect possible abbreviations on the hypothalamic-pituitary- adrenal (HPA) axis. The HPA-axis is previously linked to DNAm and the development and recovery of PTSD. Youth were treated with 8 sessions of either Eye Movement Reprocessing Therapy (EMDR) or Trauma Focused Cognitive behavioral Therapy (TF-CBT). Our epigenome wide approach showed distinct methylation between treatment responders and non-responders on C18orf63 gene post-treatment. This genomic region is related to the PAX5 gene, involved in neurodevelopment and inflammation response. Additionally, our targeted approach indicated that there were longitudinal DNAm changes in successfully treated youth at the CRHR2 gene. Methylation at this gene was further correlated with cortisol secretion pre- and post-treatment. Awaiting replication, findings of this first study in youth point to molecular pathways involved in stress response and neuroplasticity to be associated with treatment response.

Testing Quantitative and Qualitative Sex Effects in a National Swedish Twin-Sibling Study of Posttraumatic Stress Disorder.

OBJECTIVE: Twin studies have demonstrated that posttraumatic stress disorder (PTSD) is moderately heritable, and the pattern of findings across studies suggests higher heritability in females compared with males. Formal testing of sex differences has yet to be done in twin studies of PTSD. The authors sought to estimate the genetic and environmental contributions to PTSD, and to formally test for sex differences, in the largest sample to date of both sexes, among twins and siblings. METHODS: Using the Swedish National Registries, the authors performed structural equation modeling to decompose genetic and environmental variance for PTSD and to formally test for quantitative and qualitative sex differences in twins (16,242 pairs) and in full siblings within 2 years of age of each other (376,093 pairs), using diagnostic codes from medical registries. RESULTS: The best-fit model suggested that additive genetic and unique environmental effects contributed to PTSD. Evidence for a quantitative sex effect was found, such that heritability was significantly greater in females (35.4%) than males (28.6%). Evidence of a qualitative sex effect was found, such that the genetic correlation was high but less than complete (rg=0.81, 95% CI=0.73-0.89). No evidence of shared environment or special twin environment was found. CONCLUSIONS: This is the first demonstration of quantitative and qualitative sex effects for PTSD. The results suggest that unique environmental effects, but not the shared environment, contributed to PTSD and that genetic influences for the disorder are stronger in females compared with males. Although the heritability is highly correlated, it is not at unity between the sexes.

A pilot study of the role of the BDNF Val66Met polymorphism in response to exercise-augmented exposure therapy for posttraumatic stress disorder.

Brain-Derived Neurotrophic Factor (BDNF) is implicated in extinction learning, which is a primary mechanism of exposure therapy for posttraumatic stress disorder (PTSD). Brief aerobic exercise has been shown to promote BDNF release and augment extinction learning. On the premise that the Val allele of the BDNF Val66Met polymorphism facilitates greater release of BDNF, this study examined the extent to which the Val allele of the BDNF polymorphism predicted treatment response in PTSD patients who underwent exposure therapy combined with aerobic exercise or passive stretching. PTSD patients (N = 85) provided saliva samples in order to extract genomic DNA to identify Val/Val and Met carriers of the BDNF Val66Met genotype, and were assessed for PTSD severity prior to and following a 9-week course of exposure therapy combined with aerobic exercise or stretching. The sample comprised 52 Val/Val carriers and 33 Met carriers. Patients with the BDNF high-expression Val allele display greater reduction of PTSD symptoms at posttreatment than Met carriers. Hierarchical regression analysis indicated that greater PTSD reduction was specifically observed in Val/Val carriers who received exposure therapy in combination with the aerobic exercise. This finding accords with animal and human evidence that the BDNF Val allele promotes greater extinction learning, and that these individuals may benefit more from exercise-augmented extinction. Although preliminary, this result represents a possible avenue for augmented exposure therapy in patients with the BDNF Val allele.

Extended Swedish Adoption Study of Adverse Stress Responses and Posttraumatic Stress Disorder.

Importance: Twin studies have found that posttraumatic stress disorder (PTSD) is influenced by both genetic and environmental factors within a generation. No study has used an adoption design, which can address questions about the degree and sources of cross-generational transmission of adverse stress responses (ASRs) and PTSD. Objectives: To examine whether ASRs or PTSD are transmitted from parents to offspring, and to clarify the relative importance of genes and rearing. Design, Setting, and Participants: This cohort study used nationwide Swedish registry data from parents and offspring (n = 2 194 171, born 1960-1992) of 6 types of families (intact; had not lived with biological father; had not lived with biological mother; lived with stepfather; lived with stepmother; and adoptive). Follow-up occurred on December 31, 2018, and data were analyzed from March 3, 2023, to January 16, 2024. Exposures: Three sources of parent-offspring resemblance: genes plus rearing, genes only, and rearing only. Main Outcomes and Measures: Diagnoses of ASRs or PTSD were obtained from national inpatient, outpatient, and primary care medical registries. Parent-child resemblance was assessed by tetrachoric correlation. Sensitivity analyses were conducted to control for possible shared traumatic events. Results: The study population included 2 194 171 individuals of 6 family types (1 146 703 [52.3%] male; median [range] age, 42 [20-63] years). The weighted tetrachoric correlations across family types were 0.15 (95% CI, 0.15-0.16) for genes plus rearing, 0.08 (95% CI, 0.06-0.11) for genes only, and 0.10 (95% CI, 0.07-0.12) for rearing only. Controlling for potential shared traumatic events, sensitivity analyses found that the correlation for rearing decreased, with the most conservative control (exclusion of parent-offspring dyads with onset of ASRs or PTSD within 1 year) suggesting equal correlations with genes and rearing. Conclusions and Relevance: Diagnosis of ASRs or PTSD demonstrated cross-generational transmission, including both genetic and rearing correlations. Sensitivity analyses suggested that shared traumatic events partially accounted for the observed rearing correlations.

The role of SKA2 on affective disorder, post-traumatic stress disorder and suicide behavior: systematic review and in silico analysis.

Genes involved in the hypothalamic-pituitary-adrenal axis may be a robust biomarker of psychiatric disorders. Genetic polymorphisms of the SKA2 gene are associated with several behavioral disorders. In this study, we embarked on a systematic search of all possible reports of genetic association with SKA2 and affective disorder, post-traumatic stress disorder, and suicide behavior; the functional consequences of nsSNPs were explored through computational tools with an in silico analysis. Eight eligible articles were included. Our study identified that SKA2 did not show association with risk of Major Depression Disorder. Epigenetic variation at SKA2 mediates vulnerability to Post-Traumatic Stress Disorder. Studies provide strong preliminary evidence that alterations at the SKA2 gene covary with types of suicide behavior, including suicidal ideation, attempts, and completions. Results from in silico analysis predicted that I22S, I22G, I78T, A15L, D18R, R25L, N42I, Y21S, K14I, K14L, and L60R were the most structurally and functionally significant nsSNPs in SKA2. Amino acid conservation analysis revealed that the amino acids were highly conserved and some dissimilarities of mutant type amino acids from wild-type amino acids such as charge, size, and hydrophobicity were observed. In the future, SKA2 gene have the potential to be evaluated as prognostic biomarkers for diagnosis and research.

Physiological and genomic signatures of war and displacement: A comprehensive literature review and future directions.

There are now 108.4 million forcibly displaced people worldwide, many of whom endure adversities that result in trauma, toxic stress, and potentially, altered epigenetic development. This paper provides a comprehensive review of current literature on the biological signatures of war and forced migration among refugee populations. To consolidate evidence and identify key concerns and avenues for future research, we reviewed 36 publications and one article under review, published since 2000, most of which focused on refugees relocated in Europe and the Middle East. This body of work - including cross-sectional, observational, and experimental studies - reveals heterogenous findings regarding human biological responses to war-related adversities and their associations with health outcomes. We conclude with four main observations, regarding why genomic and physiological biomarkers are valuable, what study designs advance understanding of causality and health-promoting interventions, how to prepare for ethical challenges, and why theoretical frameworks and research procedures need more detailed consideration in scientific publications.

Distinguishing vulnerability and resilience to posttraumatic stress disorder evaluating traumatic experiences, genetic risk and electronic health records.

What distinguishes vulnerability and resilience to posttraumatic stress disorder (PTSD) remains unclear. Levering traumatic experiences reporting, genetic data, and electronic health records (EHR), we investigated and predicted the clinical comorbidities (co-phenome) of PTSD vulnerability and resilience in the UK Biobank (UKB) and All of Us Research Program (AoU), respectively. In 60,354 trauma-exposed UKB participants, we defined PTSD vulnerability and resilience considering PTSD symptoms, trauma burden, and polygenic risk scores. EHR-based phenome-wide association studies (PheWAS) were conducted to dissect the co-phenomes of PTSD vulnerability and resilience. Significant diagnostic endpoints were applied as weights, yielding a phenotypic risk score (PheRS) to conduct PheWAS of PTSD vulnerability and resilience PheRS in up to 95,761 AoU participants. EHR-based PheWAS revealed three significant phenotypes positively associated with PTSD vulnerability (top association "Sleep disorders") and five outcomes inversely associated with PTSD resilience (top association "Irritable Bowel Syndrome"). In the AoU cohort, PheRS analysis showed a partial inverse relationship between vulnerability and resilience with distinct comorbid associations. While PheRSvulnerability associations were linked to multiple phenotypes, PheRSresilience showed inverse relationships with eye conditions. Our study unveils phenotypic differences in PTSD vulnerability and resilience, highlighting that these concepts are not simply the absence and presence of PTSD.

Systems biology dissection of PTSD and MDD across brain regions, cell types, and blood.

The molecular pathology of stress-related disorders remains elusive. Our brain multiregion, multiomic study of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) included the central nucleus of the amygdala, hippocampal dentate gyrus, and medial prefrontal cortex (mPFC). Genes and exons within the mPFC carried most disease signals replicated across two independent cohorts. Pathways pointed to immune function, neuronal and synaptic regulation, and stress hormones. Multiomic factor and gene network analyses provided the underlying genomic structure. Single nucleus RNA sequencing in dorsolateral PFC revealed dysregulated (stress-related) signals in neuronal and non-neuronal cell types. Analyses of brain-blood intersections in >50,000 UK Biobank participants were conducted along with fine-mapping of the results of PTSD and MDD genome-wide association studies to distinguish risk from disease processes. Our data suggest shared and distinct molecular pathology in both disorders and propose potential therapeutic targets and biomarkers.

Leveraging interindividual variability in threat conditioning of inbred mice to model trait anxiety.

Trait anxiety is a major risk factor for stress-induced and anxiety disorders in humans. However, animal models accounting for the interindividual variability in stress vulnerability are largely lacking. Moreover, the pervasive bias of using mostly male animals in preclinical studies poorly reflects the increased prevalence of psychiatric disorders in women. Using the threat imminence continuum theory, we designed and validated an auditory aversive conditioning-based pipeline in both female and male mice. We operationalised trait anxiety by harnessing the naturally occurring variability of defensive freezing responses combined with a model-based clustering strategy. While sustained freezing during prolonged retrieval sessions was identified as an anxiety-endophenotype behavioral marker in both sexes, females were consistently associated with an increased freezing response. RNA-sequencing of CeA, BLA, ACC, and BNST revealed massive differences in phasic and sustained responders' transcriptomes, correlating with transcriptomic signatures of psychiatric disorders, particularly post-traumatic stress disorder (PTSD). Moreover, we detected significant alterations in the excitation/inhibition balance of principal neurons in the lateral amygdala. These findings provide compelling evidence that trait anxiety in inbred mice can be leveraged to develop translationally relevant preclinical models to investigate mechanisms of stress susceptibility in a sex-specific manner.

Differential impact of prenatal PTSD symptoms and preconception trauma exposure on placental NR3C1 and FKBP5 methylation.

Perinatal stress is associated with altered placental methylation, which plays a critical role in fetal development and infant outcomes. This proof-of-concept pilot study investigated the impact of lifetime trauma exposure and perinatal PTSD symptoms on epigenetic regulation of placenta glucocorticoid signaling genes (NR3C1 and FKBP5). Lifetime trauma exposure and PTSD symptoms during pregnancy were assessed in a racially/ethnically diverse sample of pregnant women (N = 198). Participants were categorized into three groups: (1) No Trauma (-T); (2) Trauma, No Symptoms (T - S); and (3) Trauma and Symptoms (T + S). Placental tissue was analyzed via bisulfite pyrosequencing for degree of methylation at the NR3C1 promoter and FKBP5 regulatory regions. Analyses of covariance were used to test group differences in percentages of NR3C1 and FKBP5 methylation overall and at each CpG site. We found a significant impact of PTSD symptoms on placental NR3C1 methylation. Compared to the -T group, the T + S group had greater NR3C1 methylation overall and at CpG6, CpG8, CpG9, and CpG13, but lower methylation at CpG5. The T + S group had significantly higher NR3C1 methylation overall and at CpG8 compared to the T - S group. There were no differences between the T - S group and - T group. Additionally, no group differences emerged for FKBP5 methylation. Pregnant trauma survivors with PTSD symptoms exhibited differential patterns of placental NR3C1 methylation compared to trauma survivors without PTSD symptoms and pregnant women unexposed to trauma. Results highlight the critical importance of interventions to address the mental health of pregnant trauma survivors.

Paradoxical effect of anti-inflammatory drugs on IL-6 mRNA expression in patients with PTSD during treatment.

The pathophysiology of posttraumatic stress disorder (PTSD) is associated with the activation of the innate immune system, including cytokines like interleukin 6 (IL-6). However, the role of IL-6 in the etiology and treatment of PTSD still remains elusive. We conducted a prospective controlled trial to investigate the development of IL-6 during psychosomatic treatment in individuals with PTSD in comparison with individuals without PTSD. We assessed IL-6 mRNA expression before and after 2 months of psychosomatic treatment in individuals with and without PTSD. Severities of PTSD and depressive symptoms were assessed in parallel. Linear mixed regression was applied for statistical analysis, including the factors diagnosis PTSD and pre-post treatment after subgrouping for intake of anti-inflammatory drugs. The development of IL-6 mRNA expression during treatment was affected by the use of anti-inflammatory drugs. In the subgroup without intake of anti-inflammatory drugs, no significant statistical treatment effect in individuals with and without PTSD emerged. In the subgroup of individuals taking anti-inflammatory drugs, a significant interaction effect of the factors pre-post treatment and diagnosis PTSD was observed. Whereas IL-6 mRNA expression in individuals without PTSD decreased according to amelioration of symptoms, IL-6 mRNA expression in individuals with PTSD increased significantly during treatment, in opposite direction to symptom severity. Anti-inflammatory drugs might affect IL-6 mRNA expression in individuals with PTSD in a paradoxical way. This study offers a further piece of evidence that IL-6 could be involved in the pathophysiology of PTSD and PTSD-specific immunologic molecular mechanisms.

Genome-wide association analyses identify 95 risk loci and provide insights into the neurobiology of post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 new). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (for example, GRIA1, GRM8 and CACNA1E), developmental, axon guidance and transcription factors (for example, FOXP2, EFNA5 and DCC), synaptic structure and function genes (for example, PCLO, NCAM1 and PDE4B) and endocrine or immune regulators (for example, ESR1, TRAF3 and TANK). Additional top genes influence stress, immune, fear and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation.

Effects of genetically predicted posttraumatic stress disorder on autoimmune phenotypes.

Observational studies suggest that posttraumatic stress disorder (PTSD) increases risk for various autoimmune diseases. Insights into shared biology and causal relationships between these diseases may inform intervention approaches to PTSD and co-morbid autoimmune conditions. We investigated the shared genetic contributions and causal relationships between PTSD, 18 autoimmune diseases, and 3 immune/inflammatory biomarkers. Univariate MiXeR was used to contrast the genetic architectures of phenotypes. Genetic correlations were estimated using linkage disequilibrium score regression. Bi-directional, two-sample Mendelian randomization (MR) was performed using independent, genome-wide significant single nucleotide polymorphisms; inverse variance weighted and weighted median MR estimates were evaluated. Sensitivity analyses for uncorrelated (MR PRESSO) and correlated horizontal pleiotropy (CAUSE) were also performed. PTSD was considerably more polygenic (10,863 influential variants) than autoimmune diseases (median 255 influential variants). However, PTSD evidenced significant genetic correlation with nine autoimmune diseases and three inflammatory biomarkers. PTSD had putative causal effects on autoimmune thyroid disease (p = 0.00009) and C-reactive protein (CRP) (p = 4.3 × 10-7). Inferences were not substantially altered by sensitivity analyses. Additionally, the PTSD-autoimmune thyroid disease association remained significant in multivariable MR analysis adjusted for genetically predicted inflammatory biomarkers as potential mechanistic pathway variables. No autoimmune disease had a significant causal effect on PTSD (all p values > 0.05). Although causal effect models were supported for associations of PTSD with CRP, shared pleiotropy was adequate to explain a putative causal effect of CRP on PTSD (p = 0.18). In summary, our results suggest a significant genetic overlap between PTSD, autoimmune diseases, and biomarkers of inflammation. PTSD has a putative causal effect on autoimmune thyroid disease, consistent with existing epidemiologic evidence. A previously reported causal effect of CRP on PTSD is potentially confounded by shared genetics. Together, results highlight the nuanced links between PTSD, autoimmune disorders, and associated inflammatory signatures, and suggest the importance of targeting related pathways to protect against disease and disability.