Genome-wide DNA methylation analysis of cannabis use disorder in a veteran cohort enriched for posttraumatic stress disorder.

Cannabis use has been increasing over the past decade, not only in the general US population, but particularly among military veterans. With this rise in use has come a concomitant increase in cannabis use disorder (CUD) among veterans. Here, we performed an epigenome-wide association study for lifetime CUD in an Iraq/Afghanistan era veteran cohort enriched for posttraumatic stress disorder (PTSD) comprising 2,310 total subjects (1,109 non-Hispanic black and 1,201 non-Hispanic white). We also investigated CUD interactions with current PTSD status and examined potential indirect effects of DNA methylation (DNAm) on the relationship between CUD and psychiatric diagnoses. Four CpGs were associated with lifetime CUD, even after controlling for the effects of current smoking (AHRR cg05575921, LINC00299 cg23079012, VWA7 cg22112841, and FAM70A cg08760398). Importantly, cg05575921, a CpG strongly linked to smoking, remained associated with lifetime CUD even when restricting the analysis to veterans who reported never smoking cigarettes. Moreover, CUD interacted with current PTSD to affect cg05575921 and cg23079012 such that those with both CUD and PTSD displayed significantly lower DNAm compared to the other groups. Finally, we provide preliminary evidence that AHRR cg05575921 helps explain the association between CUD and any psychiatric diagnoses, specifically mood disorders.

Development of Mobile Contingency Management for Cannabis Use Reduction.

Many interventions for cannabis use disorder (CUD) are associated with decreases in frequency and quantity of use but fail to increase overall rates of sustained abstinence. It is currently unknown whether reductions in use (in the absence of sustained abstinence) result in clinically significant improvements in functioning. The objective of this study was to refine a mobile contingency management approach to reduce cannabis use to ultimately evaluate whether reductions in frequency and quantity of cannabis are related to improvements in functional and mental health status. Three cohorts of participants (n = 18 total, n = 10 women) were enrolled and completed 2 weeks of ecological momentary assessment (EMA) during a baseline ad lib cannabis use period, followed by a 6-week reduction period. Participants completed EMA assessments multiple times per day and were prompted to provide videotaped saliva cannabis testing 2-3 times daily. Data from participants who were at least 80% adherent to all EMA prompts were analyzed (13 out of 18). During the ad lib phase, participants were using cannabis on 94% of the days and reported using a mean of 1.42 grams daily. The intervention was a mobile application that participants used to record cannabis use by saliva tests to bioverify abstinence and participants completed electronic diaries to report their grams used. During the 6-week intervention phase, participants reported reducing their use days to 47% of the days with a reported mean of .61 grams daily. In the last cohort, at least 50% of the heavy users were able to reduce their cannabis use by at least 50%. The effect of cannabis reduction (versus abstinence) is largely unknown. Observations suggest that it is possible to develop a mobile intervention to reduce cannabis use among heavy users, and this paradigm can be utilized in future work to evaluate whether reductions in cannabis use among heavy users will result in improvements in functional and mental health status.

Development and Implementation of Web-Based Safety Planning Intervention Training for Firefighter Peer Support Specialists.

Background: Recent findings indicate that firefighters may be at increased risk for death by suicide; however, there has been only limited suicide prevention work in fire service to date. Aim: The objective of this program evaluation project was to develop and evaluate a web-based Safety Planning Intervention (SPI) training course for firefighter peer support specialists. Method: Peer support specialists who completed the web-based SPI training were administered evaluation questionnaires before the training and then again at a 3-month follow-up assessment. Results: A total of 213 peer support specialists completed the SPI training. Most participants took 2-3 h to complete the training. Participants generally reported high levels of satisfaction with the course, with the vast majority (94.4%) indicating they would recommend it to their peers. Course completers also demonstrated significant gains in SPI knowledge and self-efficacy from baseline to 3-month follow-up (all p's < .001). Moreover, the percentage of participants who reported completing a safety plan with someone they suspected at being of risk for suicide increased approximately 7-fold from baseline (3.5%) to 3-month follow-up (25.2%; p < .001). Participants further reported that 97.6% of the safety plans that they completed resulted in a positive outcome. Limitations: This was a program evaluation project that did not include a control group. Thus, causality cannot be inferred. Conclusions: The present findings suggest that web-based SPI training is a feasible and scalable approach for training peer support specialists to deliver the SPI to at-risk individuals.

Large epigenome-wide association study identifies multiple novel differentially methylated CpG sites associated with suicidal thoughts and behaviors in veterans.

Introduction: The U.S. suicide mortality rate has steadily increased during the past two decades, particularly among military veterans; however, the epigenetic basis of suicidal thoughts and behaviors (STB) remains largely unknown. Methods: To address this issue, we conducted an epigenome-wide association study of DNA methylation (DNAm) of peripheral blood samples obtained from 2,712 U.S. military veterans. Results: Three DNAm probes were significantly associated with suicide attempts, surpassing the multiple testing threshold (FDR q-value <0.05), including cg13301722 on chromosome 7, which lies between the genes SLC4A2 and CDK5; cg04724646 in PDE3A; and cg04999352 in RARRES3. cg13301722 was also found to be differentially methylated in the cerebral cortex of suicide decedents in a publicly-available dataset (p = 0.03). Trait enrichment analysis revealed that the CpG sites most strongly associated with STB in the present sample were also associated with smoking, alcohol consumption, maternal smoking, and maternal alcohol consumption, whereas pathway enrichment analysis revealed significant associations with circadian rhythm, adherens junction, insulin secretion, and RAP-1 signaling, each of which was recently associated with suicide attempts in a large, independent genome-wide association study of suicide attempts of veterans. Discussion: Taken together, the present findings suggest that SLC4A2, CDK5, PDE3A, and RARRES3 may play a role in STB. CDK5, a member of the cyclin-dependent kinase family that is highly expressed in the brain and essential for learning and memory, appears to be a particularly promising candidate worthy of future study; however, additional work is still needed to replicate these finding in independent samples.

Effect of cognitive processing therapy on markers of cardiovascular risk in posttraumatic stress disorder patients: A randomized clinical trial.

OBJECTIVE: Posttraumatic stress disorder (PTSD) is associated with elevated risk of coronary heart disease (CHD); however, the effects of PTSD treatment on CHD biomarkers is unknown. This study examined whether cognitive processing therapy (CPT) improves 24-hourheart rate variability (HRV), a predictor of CHD mortality. METHODS: Individuals between the ages of 40 and 65 years with PTSD (n = 112) were randomized to receive 12 sessions of CPT or a Waiting List (WL) intervention comprised of 6 weekly telephone checks of emotional status. The primary outcome variable was 24-hour HRV estimated from the standard deviation of all normal R-R intervals (SDNN); secondary outcomes were the root mean square of successive differences between heart beats (RMSSD), low-frequency HRV (LF-HRV) and high-frequency HRV (HF-HRV). Secondary outcomes also included 24-hour urinary catecholamine excretion, plasma C-reactive protein (CRP), and flow-mediated dilation (FMD) of the brachial artery. For outcomes, linear mixed longitudinal models were used to estimate mean differences (Mdiff). RESULTS: Participants randomized to the CPT group did not show improved SDNN (Mdiff = 9.8; 95%CI, -2.7 to 22.3; p = 0.12), the primary outcome variable, but showed improved RMSSD (Mdiff = 3.8; 95% CI, 0.5 to 7.1; p = 0.02), LF- HRV (Mdiff =0.3; 95% CI, 0.1 to 0.5; p = 0.01), and HF-HRV (Mdiff = 0.3; 95% CI, 0.0 to 0.6; p = 0.03) compared to WL. There were no differences between groups in catecholamine excretion, FMD, or inflammatory markers. CONCLUSION: Treating PTSD may not only improve quality of life but may also help ameliorate heightened CHD risk characteristics of PTSD.

Genome-wide association study identifies four pan-ancestry loci for suicidal ideation in the Million Veteran Program.

Suicidal ideation (SI) often precedes and predicts suicide attempt and death, is the most common suicidal phenotype and is over-represented in veterans. The genetic architecture of SI in the absence of suicide attempt (SA) is unknown, yet believed to have distinct and overlapping risk with other suicidal behaviors. We performed the first GWAS of SI without SA in the Million Veteran Program (MVP), identifying 99,814 SI cases from electronic health records without a history of SA or suicide death (SD) and 512,567 controls without SI, SA or SD. GWAS was performed separately in the four largest ancestry groups, controlling for sex, age and genetic substructure. Ancestry-specific results were combined via meta-analysis to identify pan-ancestry loci. Four genome-wide significant (GWS) loci were identified in the pan-ancestry meta-analysis with loci on chromosomes 6 and 9 associated with suicide attempt in an independent sample. Pan-ancestry gene-based analysis identified GWS associations with DRD2, DCC, FBXL19, BCL7C, CTF1, ANNK1, and EXD3. Gene-set analysis implicated synaptic and startle response pathways (q's<0.05). European ancestry (EA) analysis identified GWS loci on chromosomes 6 and 9, as well as GWS gene associations in EXD3, DRD2, and DCC. No other ancestry-specific GWS results were identified, underscoring the need to increase representation of diverse individuals. The genetic correlation of SI and SA within MVP was high (rG = 0.87; p = 1.09e-50), as well as with post-traumatic stress disorder (PTSD; rG = 0.78; p = 1.98e-95) and major depressive disorder (MDD; rG = 0.78; p = 8.33e-83). Conditional analysis on PTSD and MDD attenuated most pan-ancestry and EA GWS signals for SI without SA to nominal significance, with the exception of EXD3 which remained GWS. Our novel findings support a polygenic and complex architecture for SI without SA which is largely shared with SA and overlaps with psychiatric conditions frequently comorbid with suicidal behaviors.

Identification of Novel, Replicable Genetic Risk Loci for Suicidal Thoughts and Behaviors Among US Military Veterans.

Importance: Suicide is a leading cause of death; however, the molecular genetic basis of suicidal thoughts and behaviors (SITB) remains unknown. Objective: To identify novel, replicable genomic risk loci for SITB. Design, Setting, and Participants: This genome-wide association study included 633 778 US military veterans with and without SITB, as identified through electronic health records. GWAS was performed separately by ancestry, controlling for sex, age, and genetic substructure. Cross-ancestry risk loci were identified through meta-analysis. Study enrollment began in 2011 and is ongoing. Data were analyzed from November 2021 to August 2022. Main Outcome and Measures: SITB. Results: A total of 633 778 US military veterans were included in the analysis (57 152 [9%] female; 121 118 [19.1%] African ancestry, 8285 [1.3%] Asian ancestry, 452 767 [71.4%] European ancestry, and 51 608 [8.1%] Hispanic ancestry), including 121 211 individuals with SITB (19.1%). Meta-analysis identified more than 200 GWS (P < 5 × 10-8) cross-ancestry risk single-nucleotide variants for SITB concentrated in 7 regions on chromosomes 2, 6, 9, 11, 14, 16, and 18. Top single-nucleotide variants were largely intronic in nature; 5 were independently replicated in ISGC, including rs6557168 in ESR1, rs12808482 in DRD2, rs77641763 in EXD3, rs10671545 in DCC, and rs36006172 in TRAF3. Associations for FBXL19 and AC018880.2 were not replicated. Gene-based analyses implicated 24 additional GWS cross-ancestry risk genes, including FURIN, TSNARE1, and the NCAM1-TTC12-ANKK1-DRD2 gene cluster. Cross-ancestry enrichment analyses revealed significant enrichment for expression in brain and pituitary tissue, synapse and ubiquitination processes, amphetamine addiction, parathyroid hormone synthesis, axon guidance, and dopaminergic pathways. Seven other unique European ancestry-specific GWS loci were identified, 2 of which (POM121L2 and METTL15/LINC02758) were replicated. Two additional GWS ancestry-specific loci were identified within the African ancestry (PET112/GATB) and Hispanic ancestry (intergenic locus on chromosome 4) subsets, both of which were replicated. No GWS loci were identified within the Asian ancestry subset; however, significant enrichment was observed for axon guidance, cyclic adenosine monophosphate signaling, focal adhesion, glutamatergic synapse, and oxytocin signaling pathways across all ancestries. Within the European ancestry subset, genetic correlations (r > 0.75) were observed between the SITB phenotype and a suicide attempt-only phenotype, depression, and posttraumatic stress disorder. Additionally, polygenic risk score analyses revealed that the Million Veteran Program polygenic risk score had nominally significant main effects in 2 independent samples of veterans of European and African ancestry. Conclusions and Relevance: The findings of this analysis may advance understanding of the molecular genetic basis of SITB and provide evidence for ESR1, DRD2, TRAF3, and DCC as cross-ancestry candidate risk genes. More work is needed to replicate these findings and to determine if and how these genes might impact clinical care.

Impact of traumatic life events and polygenic risk scores for major depression and posttraumatic stress disorder on Iraq/Afghanistan Veterans.

Traumatic experiences and genetic heritability are among the most widely acknowledged risk factors leading to the development of psychopathology; including posttraumatic stress disorder (PTSD) and major depressive disorder (MDD). The purpose of this study was to investigate if polygenic risk scores (PRS) among Veterans interacted with traumatic stress to predict PTSD and MDD. 1,389 Iraq-Afghanistan military service Veterans from the Mental Illness Research Education and Clinical Center dataset were analyzed. Genome-wide association study (GWAS) statistics were utilized to generate PRS for PTSD (PRSPTSD) and PRS for MDD (PRSMDD) in order to analyze PRS-by-environment (PRSxE) with trauma exposure to predict PTSD and MDD diagnoses. Trauma exposure and PRSPTSD, were independently associated with a current PTSD diagnosis (p < 0.001 and p < 0.001, respectively). The interaction between trauma exposure and PRSMDD to predict a current diagnosis of PTSD trended towards significance (p = 0.053). Stratifying by trauma thresholds, among those within the lowest trauma load, the association of PRSMDD with PTSD was found to be nominally significant (p = 0.03). For a MDD diagnosis, there was a significant association with trauma exposure (p < 0.001); and the association with PRSMDD was found to be nominally significant (p = 0.03). No significant PRSxE effects were found with MDD. Our findings corroborate previous research highlighting trauma exposure, and genetic heritability, as risk factors for the development of PTSD and MDD in a Veteran population. Additionally, findings suggest that genetic vulnerability may be less important as trauma exposure increases, with high levels of trauma likely to result in PTSD and MDD, regardless of genetic vulnerability.

A genome-wide association study of suicide attempts in the million veterans program identifies evidence of pan-ancestry and ancestry-specific risk loci.

To identify pan-ancestry and ancestry-specific loci associated with attempting suicide among veterans, we conducted a genome-wide association study (GWAS) of suicide attempts within a large, multi-ancestry cohort of U.S. veterans enrolled in the Million Veterans Program (MVP). Cases were defined as veterans with a documented history of suicide attempts in the electronic health record (EHR; N = 14,089) and controls were defined as veterans with no documented history of suicidal thoughts or behaviors in the EHR (N = 395,064). GWAS was performed separately in each ancestry group, controlling for sex, age and genetic substructure. Pan-ancestry risk loci were identified through meta-analysis and included two genome-wide significant loci on chromosomes 20 (p = 3.64 × 10-9) and 1 (p = 3.69 × 10-8). A strong pan-ancestry signal at the Dopamine Receptor D2 locus (p = 1.77 × 10-7) was also identified and subsequently replicated in a large, independent international civilian cohort (p = 7.97 × 10-4). Additionally, ancestry-specific genome-wide significant loci were also detected in African-Americans, European-Americans, Asian-Americans, and Hispanic-Americans. Pathway analyses suggested over-representation of many biological pathways with high clinical significance, including oxytocin signaling, glutamatergic synapse, cortisol synthesis and secretion, dopaminergic synapse, and circadian rhythm. These findings confirm that the genetic architecture underlying suicide attempt risk is complex and includes both pan-ancestry and ancestry-specific risk loci. Moreover, pathway analyses suggested many commonly impacted biological pathways that could inform development of improved therapeutics for suicide prevention.

Ambulatory Heart Rate Variability Monitoring: Comparisons Between the Empatica E4 Wristband and Holter Electrocardiogram.

OBJECTIVE: Heart rate variability (HRV) is a useful index of psychological and physiological stress. Although several wristband devices have purported to measure HRV, none have demonstrated reliability when compared with the criterion-standard Holter monitor. We evaluated the reliability of HRV readings from the Empatica E4 wristband compared with a Holter monitor over a 24-hour period of simultaneous monitoring. METHODS: Agreement between the monitors was assessed by examining correlations and intraclass correlations (ICCs) for fixed sets in 13 individuals in a treatment trial for posttraumatic stress disorder (4 women; mean [standard deviation] age = 51.92 [6.17] years). Agreement was calculated at 1-second and 5-minute intervals for interbeat intervals (IBIs) and for 5-minute intervals of the root mean square of successive differences between normal heartbeats (RMSSD) and standard deviation of all normal R-R intervals (SDNN). Agreement across the entire 24-hour observation period was also measured. Frequency-domain measures of HRV could not be calculated because of too much missing data from the E4. RESULTS: Although high interdevice correlations and ICCs were observed between the E4 and Holter monitors for IBIs at 1-second (median r = 0.88; median ICC = 0.87) and 5-minute (median r = 0.94; median ICC = 0.94) intervals, reliabilities for 5-minute RMSSD (median r = -0.09; median ICC = -0.05) and 5-minute SDNN (median r = 0.48; median ICC = 0.47) were poor. Agreement between the devices on 24-hour measures of HRV was satisfactory (IBI: r = 0.97, ICC = 0.97; RMSSD: r = 0.77, IBI = 0.76; SDNN: r = 0.92, IBI = 0.89). CONCLUSIONS: Findings suggest that the low reliability of Empatica E4 as compared with the Holter monitor does not justify its use in ambulatory research for the measurement of HRV over time periods of 5 minutes or less.

Enhancing Discovery of Genetic Variants for Posttraumatic Stress Disorder Through Integration of Quantitative Phenotypes and Trauma Exposure Information.

BACKGROUND: Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs). METHODS: A GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran Program GWAS of PTSD total symptoms. RESULTS: GWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran Program. CONCLUSIONS: Through using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods.

Gene Expression Analysis in Three Posttraumatic Stress Disorder Cohorts Implicates Inflammation and Innate Immunity Pathways and Uncovers Shared Genetic Risk With Major Depressive Disorder.

Posttraumatic stress disorder (PTSD) is a complex psychiatric disorder that can develop following exposure to traumatic events. The Psychiatric Genomics Consortium PTSD group (PGC-PTSD) has collected over 20,000 multi-ethnic PTSD cases and controls and has identified both genetic and epigenetic factors associated with PTSD risk. To further investigate biological correlates of PTSD risk, we examined three PGC-PTSD cohorts comprising 977 subjects to identify differentially expressed genes among PTSD cases and controls. Whole blood gene expression was quantified with the HumanHT-12 v4 Expression BeadChip for 726 OEF/OIF veterans from the Veterans Affairs (VA) Mental Illness Research Education and Clinical Center (MIRECC), 155 samples from the Injury and Traumatic Stress (INTRuST) Clinical Consortium, and 96 Australian Vietnam War veterans. Differential gene expression analysis was performed in each cohort separately followed by meta-analysis. In the largest cohort, we performed co-expression analysis to identify modules of genes that are associated with PTSD and MDD. We then conducted expression quantitative trait loci (eQTL) analysis and assessed the presence of eQTL interactions involving PTSD and major depressive disorder (MDD). Finally, we utilized PTSD and MDD GWAS summary statistics to identify regions that colocalize with eQTLs. Although not surpassing correction for multiple testing, the most differentially expressed genes in meta-analysis were interleukin-1 beta (IL1B), a pro-inflammatory cytokine previously associated with PTSD, and integrin-linked kinase (ILK), which is highly expressed in brain and can rescue dysregulated hippocampal neurogenesis and memory deficits. Pathway analysis revealed enrichment of toll-like receptor (TLR) and interleukin-1 receptor genes, which are integral to cellular innate immune response. Co-expression analysis identified four modules of genes associated with PTSD, two of which are also associated with MDD, demonstrating common biological pathways underlying the two conditions. Lastly, we identified four genes (UBA7, HLA-F, HSPA1B, and RERE) with high probability of a shared causal eQTL variant with PTSD and/or MDD GWAS variants, thereby providing a potential mechanism by which the GWAS variant contributes to disease risk. In summary, we provide additional evidence for genes and pathways previously reported and identified plausible novel candidates for PTSD. These data provide further insight into genetic factors and pathways involved in PTSD, as well as potential regions of pleiotropy between PTSD and MDD.

Examining Individual and Synergistic Contributions of PTSD and Genetics to Blood Pressure: A Trans-Ethnic Meta-Analysis.

Growing research suggests that posttraumatic stress disorder (PTSD) may be a risk factor for poor cardiovascular health, and yet our understanding of who might be at greatest risk of adverse cardiovascular outcomes after trauma is limited. In this study, we conducted the first examination of the individual and synergistic contributions of PTSD symptoms and blood pressure genetics to continuous blood pressure levels. We harnessed the power of the Psychiatric Genomics Consortium-PTSD Physical Health Working Group and investigated these associations across 11 studies of 72,224 trauma-exposed individuals of European (n = 70,870) and African (n = 1,354) ancestry. Genetic contributions to blood pressure were modeled via polygenic scores (PGS) for systolic blood pressure (SBP) and diastolic blood pressure (DBP) that were derived from a prior trans-ethnic blood pressure genome-wide association study (GWAS). Results of trans-ethnic meta-analyses revealed significant main effects of the PGS on blood pressure levels [SBP: ß = 2.83, standard error (SE) = 0.06, p < 1E-20; DBP: ß = 1.32, SE = 0.04, p < 1E-20]. Significant main effects of PTSD symptoms were also detected for SBP and DBP in trans-ethnic meta-analyses, though there was significant heterogeneity in these results. When including data from the largest contributing study - United Kingdom Biobank - PTSD symptoms were negatively associated with SBP levels (ß = -1.46, SE = 0.44, p = 9.8E-4) and positively associated with DBP levels (ß = 0.70, SE = 0.26, p = 8.1E-3). However, when excluding the United Kingdom Biobank cohort in trans-ethnic meta-analyses, there was a nominally significant positive association between PTSD symptoms and SBP levels (ß = 2.81, SE = 1.13, p = 0.01); no significant association was observed for DBP (ß = 0.43, SE = 0.78, p = 0.58). Blood pressure PGS did not significantly moderate the associations between PTSD symptoms and blood pressure levels in meta-analyses. Additional research is needed to better understand the extent to which PTSD is associated with high blood pressure and how genetic as well as contextual factors may play a role in influencing cardiovascular risk.

The effect of reducing posttraumatic stress disorder symptoms on cardiovascular risk: Design and methodology of a randomized clinical trial.

Posttraumatic stress disorder (PTSD) has been associated with accelerated progression of coronary heart disease (CHD). However, the underlying pathophysiological pathway has remained elusive and it is unclear whether there is a direct link between PTSD and CHD risk. This paper describes the methods of a randomized controlled trial developed to examine how changes in PTSD symptoms affect CHD disease pathways. One hundred twenty participants with current PTSD and who are free of known CHD will be randomized to receive either an evidence-based treatment for PTSD (Cognitive Processing Therapy; CPT) or a waitlist control (WL). Before and after CPT/WL, participants undergo assessment of CHD risk biomarkers reflecting autonomic nervous system dysregulation, systemic inflammation, and vascular endothelial dysfunction. The primary hypothesis is that individuals who show improvement in PTSD symptoms will show improvement in CHD risk biomarkers, whereas individuals who fail to improve or show worsening PTSD symptoms will have no change or worsening in CHD biomarkers. This study is expected to provide knowledge of the role of both the direct impact of PTSD symptoms on CHD risk pathways and the role of these systems as candidate mechanisms underlying the relationship between PTSD and CHD risk. Further, results will provide guidance on the utility of cognitive therapy as a tool to mitigate the accelerated progression of CHD in PTSD. Clinical Trials Registration: https://clinicaltrials.gov/ct2/show/NCT02736929; Unique identifier: NCT02736929.

Genetic predictors of hippocampal subfield volume in PTSD cases and trauma-exposed controls.

Behavioural, structural, and functional neuroimaging have implicated the hippocampus as a critical brain region in posttraumatic stress disorder (PTSD) pathogenesis. Recent work in a normative, primarily European, sample identified 15 unique genetic loci contributing to structural variability in six hippocampal subfield volumes. We explored the relevance of these loci in two samples (Mental Illness Research Education and Clinical Centre [MIRECC] and Grady; n = 290) of trauma-exposed individuals enriched for PTSD and of diverse ancestry. Four of the previous loci demonstrated nominal evidence of replication in the MIRECC dataset, primarily within non-Hispanic whites (NHW). One locus replicated in the Grady cohort, which was composed exclusively of non-Hispanic blacks (NHB). Our data supported genetic interactions with diagnosis of lifetime PTSD and genetic interactions with childhood trauma in the MIRECC sample, but not the Grady sample. Given the racial, diagnostic, and trauma-exposure differences with the original genome-wide association study (GWAS) report, we conducted a full GWAS in the MIRECC and Grady datasets. Interactions between genetic variants and lifetime PTSD or childhood trauma were interrogated for single nucleotide polymorphisms (SNPs) with evidence of main effects. Genetic associations surpassed false discovery rate (FDR)-correction within hippocampal subfields in fimbria, subiculum, cornu ammonis-1 (CA1), and hippocampal amygdala transition area (HATA). One association was replicated in the Grady cohort (rs12880795 in TUNAR with left (L)-HATA volume). The most significant association in the MIRECC dataset was between rs6906714 in LINC02571 and right (R)-fimbria volume (p = 5.99×10-8, q = 0.0056). Interestingly, the effect of rs6906714 on R-fimbria volume increased with exposure to childhood trauma (gene*environment [G*E] interaction p = 0.022). These preliminary results argue for G*E interactions between genetic loci with PTSD and childhood trauma on hippocampal phenotypes. Our results underscore the need for larger neuroimaging-genetic studies in PTSD, trauma, and ancestrally diverse populations.

Las neuroimagenologia, conductual, estructural y funcional ha implicado que el hipocampo se constituye como una región cerebral critica en la patogénesis del trastorno de estrés postraumático (TEPT). Un trabajo reciente, realizado en una muestra normativa, principalmente europea, identifico 15 loci genéticos únicos que contribuyen a la variabilidad estructural de seis volúmenes de subcampos hipocampales. Exploramos la relevancia de estos loci en dos muestras enriquecidas para TEPT (del Centro de Educación y Clínica Investigación sobre Enfermedades Mentales, MIRECC por sus siglas en inglés y Grady; n=290) de individuos expuestos a trauma y de ascendencia diversa. Cuatro de los loci previos demostraron evidencia nominal de replicación en la base de datos MIRECC, principalmente en personas de raza blanca no hispánicos (NHW). Se replicó un locus en la cohorte Grady, que estaba compuesta exclusivamente por personas de raza negra no hispánicos (NHB). Nuestros datos respaldaron las interacciones genéticas con el diagnostico de TEPT a lo largo de la vida e interacciones genéticas con trauma infantil en la muestra MIRECC, pero no en la de Grady. Debido a las diferencias raciales, diagnósticas y de exposición a trauma con el reporte original del estudio de asociación del genoma completo (GWAS por sus siglas en ingles), realizamos un GWAS completo con la base de datos MIRECC y Grady. Se exploraron polimorfismos de nucleótido único (SNPs por sus siglas en ingles) en las interacciones de variantes genéticas del TEPT a lo largo de la vida y del trauma infantil, con evidencia de un efecto genético principal. Las asociaciones genéticas sobrepasaron a la corrección de tasa de falso descubrimiento (FDR) dentro de los subcampos hipocampales de la fimbria, subículo, asta de Amon-1 (CA1), y el área de transición hipocampo-amigdaliana (HATA). Una asociación se replicó en la cohorte de Grady (rs 12880795 en TUNAR con volumen izquierdo del HATA). La asociación más significativa en la base de datos de MIRECC estuvo entre rs6906714 en LINC02571 y el volumen de la fimbria derecha (p=5.99×10-8, q=0.0056). Interesantemente, el efecto rs6906714 sobre el volumen de la fimbria derecha se incrementaba con la exposición al trauma infantil (interacción gen* ambiente [G*A] p=0.022). Estos resultados preliminares orientarían a la presencia de interacciones G*A de loci genéticos con el TEPT y trauma infantil en fenotipos del hipocampo. Nuestro resultados destacan la necesidad de estudios más grandes que vinculen neuroimagenes y genética en poblaciones con TEPT, trauma, y genealogía diversa.

Negative Affect-Related Autonomic Arousal Mediates the Association between Baroreflex Dysfunction and Insulin Resistance in Non-Diabetic Young Adults.

Autonomic dysfunction, in particular under-regulation of heart rate (HR) by the baroreflex, is implicated in development of insulin resistance (IR). According to reactivity hypothesis, sympathetic response to stressors may be more sensitive at predicting IR than baroreceptor sensitivity (BRS), a baseline measure of baroreflex functioning. Using ecological momentary assessment (EMA) of negative affect coupled with minute-to-minute HR and heart-rate variability (HRV) monitoring, we examined whether negative affect (NA)-related autonomic arousal mediates the association of BRS with IR. At baseline, BRS was measured, and fasting serum glucose and insulin levels were collected from 178 young adults (18-39 years old), from which homeostasis model assessment of IR (HOMA-IR) and beta-cell functioning (HOMA %B) were derived. Participants subsequently underwent one day of Holter HR and HRV monitoring while reporting negative affect levels via EMA. Multilevel modeling was used to assess the associations of momentary negative affect with HR and low- (LF) and high-frequency (HF) HRV during the 5-minute intervals following each EMA reading. Structural equation modeling was then used to determine whether individual differences in these associations mediated the association of BRS with IR, measured by HOMA-IR, HOMA %B, and insulin levels. As predicted, BRS was negatively associated with the IR (ß = -.17, p = .024). However, NA-related autonomic arousal mediated their association, accounting for 56% of the covariance between BRS and IR. Not only do these results provide support for reactivity hypothesis, they reveal a potential point of intervention in the treatment of affective dysregulation.

International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci.

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations.

Cannabis Use Disorder and Post-Deployment Suicide Attempts in Iraq/Afghanistan-Era Veterans.

The objective of the present study was to use retrospective data to test the hypothesis that cannabis dependence would be associated with an increased rate of post-deployment suicide attempts. Participants included 319 veterans who had deployed to either Iraq or Afghanistan. Study procedures involved completion of a structured clinical interview and a battery of self-report questionnaires. As expected, lifetime cannabis dependence was significantly associated with post-deployment suicide attempts, AOR = 7.963, p = .014, even after controlling for the effects of pre-deployment suicide attempts, posttraumatic stress disorder, depression, pain, non-cannabis substance use disorder, and gender. Although preliminary, our findings provide the first evidence to date that heavy cannabis use may be a unique risk factor for post-deployment suicide attempts among veterans.

A genome-wide association study of suicide attempts and suicidal ideation in U.S. military veterans.

Death by suicide and suicidal behavior are major concerns among U.S. military veterans; however, no genome-wide association studies (GWAS) studies of suicidal behavior have been conducted among U.S. military veterans to date, despite the elevated rate of suicidal behavior observed within this population. Accordingly, the primary objective of the present research was to conduct the first GWAS of suicide attempts and suicidal ideation in a large and well-characterized sample of U.S. military veterans. The gene most significantly associated (p = 9.28 × 10-7) with suicide attempts was the Potassium Calcium-Activated Channel Subfamily M Regulatory Beta Subunit 2 (KCNMB2) gene, which plays a key role in neuronal excitability. In addition, replication analyses provided additional support for the potential role of the ABI Family Member 3 Binding Protein (ABI3BP) gene in the pathogenesis of suicidal behavior, as numerous nominal associations were found between this gene and both suicide attempts and suicidal ideation. Additional work aimed at replicating and extending these findings is needed.

A Randomized Clinical Trial of Nicotine Preloading for Smoking Cessation in People with Posttraumatic Stress Disorder.

OBJECTIVE: The aim of this research was to determine whether augmenting standard smoking cessation treatment by wearing an active nicotine patch before the smoking quit date improves rates of smoking cessation in individuals with posttraumatic stress disorder (PTSD) and to explore mechanisms of treatment response such as decreased cigarette craving and symptom relief from smoking. METHODS: This was a double-blind parallel randomized controlled trial in 81 people with PTSD who smoked cigarettes. Participants were recruited from Veterans Affairs outpatient clinics and flyers in the community. Participants provided ecological momentary assessments (EMAs) of PTSD symptoms, smoking withdrawal symptoms, and cravings before and after smoking a cigarette during one week of ad lib smoking and then three weeks of either a nicotine patch (n = 37) or placebo patch (n = 44) preceding the quit date. All participants received standard pharmacotherapy and behavioral treatment for smoking cessation after the quit date. To test the efficacy of nicotine patch preloading for engaging proposed treatment targets during the pre-quit phases, we used multilevel models to compare post-smoking changes in symptoms and cravings during the preloading phases to post-smoking changes reported during the ad lib smoking phase. RESULTS: There was no significant difference in quit rates across the two conditions on the primary outcome of seven-day point prevalence smoking abstinence bioverified with breath carbon monoxide at six weeks post-quit date. In a multivariable multilevel model pre- to post-cigarette changes in PTSD symptom clusters, smoking withdrawal symptoms, and cravings, there was a significant interaction between treatment phase and condition. Relative to participants in the placebo condition, participants in the nicotine patch condition experienced diminished relief from PTSD reexperiencing symptoms, smoking withdrawal symptoms, and cigarette craving after smoking a cigarette. CONCLUSIONS: Relative to placebo patch preloading, nicotine patch preloading diminished the reinforcing effects of smoking cigarettes. However, the low quit rates in both conditions suggest that nicotine patch preloading is not a sufficiently intensive treatment for achieving smoking cessation in people with PTSD. TRIAL REGISTRATION: clinicaltrials.gov: NCT00625131.