Genetic structure correlates with ethnolinguistic diversity in eastern and southern Africa.

African populations are the most diverse in the world yet are sorely underrepresented in medical genetics research. Here, we examine the structure of African populations using genetic and comprehensive multi-generational ethnolinguistic data from the Neuropsychiatric Genetics of African Populations-Psychosis study (NeuroGAP-Psychosis) consisting of 900 individuals from Ethiopia, Kenya, South Africa, and Uganda. We find that self-reported language classifications meaningfully tag underlying genetic variation that would be missed with consideration of geography alone, highlighting the importance of culture in shaping genetic diversity. Leveraging our uniquely rich multi-generational ethnolinguistic metadata, we track language transmission through the pedigree, observing the disappearance of several languages in our cohort as well as notable shifts in frequency over three generations. We find suggestive evidence for the rate of language transmission in matrilineal groups having been higher than that for patrilineal ones. We highlight both the diversity of variation within Africa as well as how within-Africa variation can be informative for broader variant interpretation; many variants that are rare elsewhere are common in parts of Africa. The work presented here improves the understanding of the spectrum of genetic variation in African populations and highlights the enormous and complex genetic and ethnolinguistic diversity across Africa.

Three Things We Learned Along the Way: lessons for training in psychiatric epidemiology.

The COVID-19 pandemic, and its associated mortality, morbidity, deep social and economic impacts was a global traumatic stressor that challenged population mental health and our de-facto mental health care system in unprecedented ways. Yet in many respects, this 'crisis' is not new. Psychiatric epidemiologists have recognized for decades the need and unmet need of people in distress and the limits of the public mental health services in the United States. We argue that psychiatric epidemiologists have a critical role to play as we endeavor to address population mental health and draw attention to three areas of consideration: the need to elevate population based solutions; engaging equitably with lived experience; and interrogating recovery. Psychiatric epidemiology has a long history of both responding to and shaping our understandings of the relationships among psychiatric disorders and society through evolving methods and training, and the current socio-historical moment again suggests that shifts in our practice can strengthen our field and its impact.

Low-coverage sequencing cost-effectively detects known and novel variation in underrepresented populations.

Genetic studies in underrepresented populations identify disproportionate numbers of novel associations. However, most genetic studies use genotyping arrays and sequenced reference panels that best capture variation most common in European ancestry populations. To compare data generation strategies best suited for underrepresented populations, we sequenced the whole genomes of 91 individuals to high coverage as part of the Neuropsychiatric Genetics of African Population-Psychosis (NeuroGAP-Psychosis) study with participants from Ethiopia, Kenya, South Africa, and Uganda. We used a downsampling approach to evaluate the quality of two cost-effective data generation strategies, GWAS arrays versus low-coverage sequencing, by calculating the concordance of imputed variants from these technologies with those from deep whole-genome sequencing data. We show that low-coverage sequencing at a depth of ≥4× captures variants of all frequencies more accurately than all commonly used GWAS arrays investigated and at a comparable cost. Lower depths of sequencing (0.5-1×) performed comparably to commonly used low-density GWAS arrays. Low-coverage sequencing is also sensitive to novel variation; 4× sequencing detects 45% of singletons and 95% of common variants identified in high-coverage African whole genomes. Low-coverage sequencing approaches surmount the problems induced by the ascertainment of common genotyping arrays, effectively identify novel variation particularly in underrepresented populations, and present opportunities to enhance variant discovery at a cost similar to traditional approaches.

Childhood maltreatment and health in the UK Biobank: triangulation of outcome-wide and polygenic risk score analyses.

BACKGROUND: Childhood maltreatment is common globally and impacts morbidity, mortality, and well-being. Our understanding of its impact is constrained by key substantive and methodological limitations of extant research, including understudied physical health outcomes and bias due to unmeasured confounding. We address these limitations through a large-scale outcome-wide triangulation study. METHODS: We performed two outcome-wide analyses (OWAs) in the UK Biobank. First, we examined the relationship between self-reported maltreatment exposure (number of maltreatment types, via Childhood Trauma Screener) and 414 outcomes in a sub-sample of 157,316 individuals using generalized linear models ("observational OWA"). Outcomes covered a broad range of health themes including health behaviors, cardiovascular disease, digestive health, socioeconomic status, and pain. Second, we examined the relationship between a polygenic risk score for maltreatment and 298 outcomes in a non-overlapping sample of 243,006 individuals ("genetic OWA"). We triangulated results across OWAs based on differing sources of bias. RESULTS: Overall, 23.8% of the analytic sample for the observational OWA reported at least one maltreatment type. Of 298 outcomes examined in both OWAs, 25% were significant in both OWAs and concordant in the direction of association. Most of these were considered robust in the observational OWA according to sensitivity analyses and included outcomes such as marital separation (OR from observational OWA, ORo = 1.25 (95% CI: 1.21, 1.29); OR from genetic OWA, ORg = 1.06 (1.03, 1.08)), major diet changes due to illness (ORo = 1.27 (1.24, 1.29); ORg = 1.01 (1.00, 1.03)), certain intestinal diseases (ORo = 1.14 (1.10, 1.18); ORg = 1.03 (1.01, 1.06)), hearing difficulty with background noise (ORo = 1.11 (1.11, 1.12); ORg = 1.01 (1.00, 1.01)), knee arthrosis (ORo = 1.13 (1.09, 1.18); ORg = 1.03 (1.01, 1.05)), frequent sleeplessness (ORo = 1.21 (1.20, 1.23); ORg = 1.02 (1.01, 1.03)), and low household income (ORo = 1.28 (1.26, 1.31); ORg = 1.02 (1.01, 1.03)). Approximately 62% of results were significant in the observational OWA but not the genetic OWA, including numerous cardiovascular outcomes. Only 6 outcomes were significant in the genetic OWA and null in the observational OWA; these included diastolic blood pressure and glaucoma. No outcomes were statistically significant in opposite directions in the two analyses, and 11% were not significant in either OWA. CONCLUSIONS: Our findings underscore the far-reaching negative effects of childhood maltreatment in later life and the utility of an outcome-wide triangulation design with sensitivity analyses for improving causal inference.

Post-traumatic stress disorder symptom remission and cognition in a large cohort of civilian women.

BACKGROUND: Post-traumatic stress disorder (PTSD) is associated with cognitive impairments. It is unclear whether problems persist after PTSD symptoms remit. METHODS: Data came from 12 270 trauma-exposed women in the Nurses' Health Study II. Trauma and PTSD symptoms were assessed using validated scales to determine PTSD status as of 2008 (trauma/no PTSD, remitted PTSD, unresolved PTSD) and symptom severity (lifetime and past-month). Starting in 2014, cognitive function was assessed using the Cogstate Brief Battery every 6 or 12 months for up to 24 months. PTSD associations with baseline cognition and longitudinal cognitive changes were estimated by covariate-adjusted linear regression and linear mixed-effects models, respectively. RESULTS: Compared to women with trauma/no PTSD, women with remitted PTSD symptoms had a similar cognitive function at baseline, while women with unresolved PTSD symptoms had worse psychomotor speed/attention and learning/working memory. In women with unresolved PTSD symptoms, past-month PTSD symptom severity was inversely associated with baseline cognition. Over follow-up, both women with remitted and unresolved PTSD symptoms in 2008, especially those with high levels of symptoms, had a faster decline in learning/working memory than women with trauma/no PTSD. In women with remitted PTSD symptoms, higher lifetime PTSD symptom severity was associated with a faster decline in learning/working memory. Results were robust to the adjustment for sociodemographic, biobehavioral, and health factors and were partially attenuated when adjusted for depression. CONCLUSION: Unresolved but not remitted PTSD was associated with worse cognitive function assessed six years later. Accelerated cognitive decline was observed among women with either unresolved or remitted PTSD symptoms.

Associations of alcohol and cannabis use with change in posttraumatic stress disorder and depression symptoms over time in recently trauma-exposed individuals.

BACKGROUND: Several hypotheses may explain the association between substance use, posttraumatic stress disorder (PTSD), and depression. However, few studies have utilized a large multisite dataset to understand this complex relationship. Our study assessed the relationship between alcohol and cannabis use trajectories and PTSD and depression symptoms across 3 months in recently trauma-exposed civilians. METHODS: In total, 1618 (1037 female) participants provided self-report data on past 30-day alcohol and cannabis use and PTSD and depression symptoms during their emergency department (baseline) visit. We reassessed participant's substance use and clinical symptoms 2, 8, and 12 weeks posttrauma. Latent class mixture modeling determined alcohol and cannabis use trajectories in the sample. Changes in PTSD and depression symptoms were assessed across alcohol and cannabis use trajectories via a mixed-model repeated-measures analysis of variance. RESULTS: Three trajectory classes (low, high, increasing use) provided the best model fit for alcohol and cannabis use. The low alcohol use class exhibited lower PTSD symptoms at baseline than the high use class; the low cannabis use class exhibited lower PTSD and depression symptoms at baseline than the high and increasing use classes; these symptoms greatly increased at week 8 and declined at week 12. Participants who already use alcohol and cannabis exhibited greater PTSD and depression symptoms at baseline that increased at week 8 with a decrease in symptoms at week 12. CONCLUSIONS: Our findings suggest that alcohol and cannabis use trajectories are associated with the intensity of posttrauma psychopathology. These findings could potentially inform the timing of therapeutic strategies.

Sex-dependent differences in vulnerability to early risk factors for posttraumatic stress disorder: results from the AURORA study.

BACKGROUND: Knowledge of sex differences in risk factors for posttraumatic stress disorder (PTSD) can contribute to the development of refined preventive interventions. Therefore, the aim of this study was to examine if women and men differ in their vulnerability to risk factors for PTSD. METHODS: As part of the longitudinal AURORA study, 2924 patients seeking emergency department (ED) treatment in the acute aftermath of trauma provided self-report assessments of pre- peri- and post-traumatic risk factors, as well as 3-month PTSD severity. We systematically examined sex-dependent effects of 16 risk factors that have previously been hypothesized to show different associations with PTSD severity in women and men. RESULTS: Women reported higher PTSD severity at 3-months post-trauma. Z-score comparisons indicated that for five of the 16 examined risk factors the association with 3-month PTSD severity was stronger in men than in women. In multivariable models, interaction effects with sex were observed for pre-traumatic anxiety symptoms, and acute dissociative symptoms; both showed stronger associations with PTSD in men than in women. Subgroup analyses suggested trauma type-conditional effects. CONCLUSIONS: Our findings indicate mechanisms to which men might be particularly vulnerable, demonstrating that known PTSD risk factors might behave differently in women and men. Analyses did not identify any risk factors to which women were more vulnerable than men, pointing toward further mechanisms to explain women's higher PTSD risk. Our study illustrates the need for a more systematic examination of sex differences in contributors to PTSD severity after trauma, which may inform refined preventive interventions.

Internal capsule microstructure mediates the relationship between childhood maltreatment and PTSD following adulthood trauma exposure.

Childhood trauma is a known risk factor for trauma and stress-related disorders in adulthood. However, limited research has investigated the impact of childhood trauma on brain structure linked to later posttraumatic dysfunction. We investigated the effect of childhood trauma on white matter microstructure after recent trauma and its relationship with future posttraumatic dysfunction among trauma-exposed adult participants (n = 202) recruited from emergency departments as part of the AURORA Study. Participants completed self-report scales assessing prior childhood maltreatment within 2-weeks in addition to assessments of PTSD, depression, anxiety, and dissociation symptoms within 6-months of their traumatic event. Fractional anisotropy (FA) obtained from diffusion tensor imaging (DTI) collected at 2-weeks and 6-months was used to index white matter microstructure. Childhood maltreatment load predicted 6-month PTSD symptoms (b = 1.75, SE = 0.78, 95% CI = [0.20, 3.29]) and inversely varied with FA in the bilateral internal capsule (IC) at 2-weeks (p = 0.0294, FDR corrected) and 6-months (p = 0.0238, FDR corrected). We observed a significant indirect effect of childhood maltreatment load on 6-month PTSD symptoms through 2-week IC microstructure (b = 0.37, Boot SE = 0.18, 95% CI = [0.05, 0.76]) that fully mediated the effect of childhood maltreatment load on PCL-5 scores (b = 1.37, SE = 0.79, 95% CI = [-0.18, 2.93]). IC microstructure did not mediate relationships between childhood maltreatment and depressive, anxiety, or dissociative symptomatology. Our findings suggest a unique role for IC microstructure as a stable neural pathway between childhood trauma and future PTSD symptoms following recent trauma. Notably, our work did not support roles of white matter tracts previously found to vary with PTSD symptoms and childhood trauma exposure, including the cingulum bundle, uncinate fasciculus, and corpus callosum. Given the IC contains sensory fibers linked to perception and motor control, childhood maltreatment might impact the neural circuits that relay and process threat-related inputs and responses to trauma.

The cumulative impact of trauma, chronic illness, and COVID-19 stress on mental health in a case-control study of adults with psychotic disorders in Ethiopia.

BACKGROUND: The COVID-19 pandemic has profoundly impacted the economic, psychological, and social well-being of people in Ethiopia. Pandemic-related fears can exacerbate anxiety and depression symptoms among those with pre-existing physical and mental health conditions as well as those with prior exposure to traumatic events. METHODS: We used data from the Ethiopia NeuroGAP-Psychosis study (898 cases and 941 controls with and without a diagnosis of psychosis respectively, 66% male, mean age = 37 years). Data was collected between November 2021 and June 2022 during the COVID-19 pandemic from four hospitals in Ethiopia (three in Addis Ababa and one in Jimma city). Structural equation modeling analysis was conducted to examine the associations between trauma exposure, physical health conditions (like arthristis, neurological disorders, diabetes), COVID-19 stress, and psychological distress (depression and anxiety symptoms). We assessed direct and indirect effects for mediation, and conducted multigroup analysis to examine moderation by case control status. RESULTS: We found evidence that the impact of greater trauma exposure and physical health conditions on higher psychological distress was mediated through higher COVID-19 stress. Sociodemographic characteristics (older age and being maried) were associated with higher psychological distress, with these associations mediated through greater trauma, physical health conditions, and COVID-19 stress. Case-control status also moderated the associations between these variables, with the mediation effects being stronger in cases and weaker in controls. Further, cases reported greater trauma and psychological distress, while controls reported more physical health conditions and COVID-19 stress. IMPLICATIONS: Our findings uniquely assess the interaction of health and emergency related factors in understudied settings like Ethiopia. They underscore the importance of including daily hardships and environmental stressors, along with prior trauma exposure, as risk factors for the assessment of mental health symptoms. This study has key implications for mental health screening and intervention research in response to complex emergency contexts like Ethiopia with a history of armed conflict in addition to the COVID-19 pandemic. Our findings can aid the development of targeted services that address the mental health of at-risk groups with pre-existing mental and physical health conditions.

Relationships between trauma types and psychotic symptoms: A network analysis of patients with psychotic disorders in a large, multi-country study in East Africa.

BACKGROUND: The link between trauma exposure and psychotic disorders is well-established. Further, specific types of trauma may be associated with specific psychotic symptoms. Network analysis is an approach that can advance our understanding of the associations across trauma types and psychotic symptoms. METHODS: We conducted a network analysis with data from 16,628 adult participants (mean age [standard deviation] = 36.3 years [11.5]; 55.8% males) with psychotic disorders in East Africa recruited between 2018 and 2023. We used the Life Events Checklist and the Mini International Neuropsychiatric Interview to determine whether specific trauma types experienced over the life course and specific psychotic symptoms were connected. We used an Ising model to estimate the network connections and bridge centrality statistics to identify nodes that may influence trauma types and psychotic symptoms. RESULTS: The trauma type "exposure to a war zone" had the highest bridge strength, betweenness, and closeness. The psychotic symptom "odd or unusual beliefs" had the second highest bridge strength. Exposure to a war zone was directly connected to visual hallucinations, odd or unusual beliefs, passivity phenomena, and disorganized speech. Odd or unusual beliefs were directly connected to transportation accidents, physical assault, war, and witnessing sudden accidental death. CONCLUSION: Specific trauma types and psychotic symptoms may interact bidirectionally. Screening for psychotic symptoms in patients with war-related trauma and evaluating lifetime trauma in patients with odd or unusual beliefs in clinical care may be considered points of intervention to limit stimulating additional psychotic symptoms and trauma exposure. This work reaffirms the importance of trauma-informed care for patients with psychotic disorders.

Psychological resilience predicting cardiometabolic conditions in adulthood in the Midlife in the United States Study.

Early adversity is associated with poor cardiometabolic health, potentially via psychological distress. However, not everyone exposed to adversity develops significant distress. Psychological resilience and positive psychological health despite adversity may protect against unfavorable cardiometabolic outcomes that are otherwise more likely. We examined early adversity, psychological resilience, and cardiometabolic risk among 3,254 adults in the Midlife in the United States Study. Psychological resilience was defined according to both early psychosocial adversity and adult psychological health (characterized by low distress and high wellbeing) at Wave 1 (1994 to 1995). Categorical resilience was derived by cross-classifying adversity (exposed versus unexposed) and psychological health (higher versus lower). We also assessed count of adversities experienced and psychological symptoms as separate variables. Incident cardiometabolic conditions (e.g., heart attack, stroke, and diabetes) were self-reported at Waves 2 (2004 to 2005) and 3 (2013 to 2014). Secondary analyses examined biological cardiometabolic risk using a composite of biomarkers available within a Wave-2 subsample. Logistic and Poisson regressions evaluated associations of resilience with cardiometabolic health across 20 follow-up y, adjusting for relevant covariates. In this initially healthy sample, nonresilient (adversity-exposed, lower psychological health) versus resilient (adversity-exposed, high psychological health) individuals had 43% higher odds of cardiometabolic conditions (95% CI 1.10 to 1.85). Odds of cardiometabolic conditions were similar among resilient versus unexposed, psychologically healthy individuals. More adversity experiences were associated with increased odds, while better psychological health with decreased odds of cardiometabolic conditions, and effects were largely independent. Patterns were similar for objectively assessed cardiometabolic risk. Psychological resilience in midlife may protect against negative cardiometabolic impacts of early adversity.

Shared genetic influences on depression and menopause symptoms.

BACKGROUND: Women experience major depression and post-traumatic stress disorder (PTSD) approximately twice as often as men. Estrogen is thought to contribute to sex differences in these disorders, and reduced estrogen is also known to be a key driver of menopause symptoms such as hot flashes. Moreover, estrogen is used to treat menopause symptoms. In order to test for potential shared genetic influences between menopause symptoms and psychiatric disorders, we conducted a genome-wide association study (GWAS) of estrogen medication use (as a proxy for menopause symptoms) in the UK Biobank. METHODS: The analysis included 232 993 women aged 39-71 in the UK Biobank. The outcome variable for genetic analyses was estrogen medication use, excluding women using hormonal contraceptives. Trans-ancestry GWAS meta-analyses were conducted along with genetic correlation analyses on the European ancestry GWAS results. Hormone usage was also tested for association with depression and PTSD. RESULTS: GWAS of estrogen medication use (compared to non-use) identified a locus in the TACR3 gene, which was previously linked to hot flashes in menopause [top rs77322567, odds ratio (OR) = 0.78, p = 7.7 × 10-15]. Genetic correlation analyses revealed shared genetic influences on menopause symptoms and depression (rg = 0.231, s.e.= 0.055, p = 2.8 × 10-5). Non-genetic analyses revealed higher psychiatric symptoms scores among women using estrogen medications. CONCLUSIONS: These results suggest that menopause symptoms have a complex genetic etiology which is partially shared with genetic influences on depression. Moreover, the TACR3 gene identified here has direct clinical relevance; antagonists for the neurokinin 3 receptor (coded for by TACR3) are effective treatments for hot flashes.

Depression, worry, and loneliness are associated with subsequent risk of hospitalization for COVID-19: a prospective study.

BACKGROUND: Pre-pandemic psychological distress is associated with increased susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but associations with the coronavirus disease 2019 (COVID-19) severity are not established. The authors examined the associations between distress prior to SARS-CoV-2 infection and subsequent risk of hospitalization. METHODS: Between April 2020 (baseline) and April 2021, we followed 54 781 participants from three ongoing cohorts: Nurses' Health Study II (NHSII), Nurses' Health Study 3 (NHS3), and the Growing Up Today Study (GUTS) who reported no current or prior SARS-CoV-2 infection at baseline. Chronic depression was assessed during 2010-2019. Depression, anxiety, worry about COVID-19, perceived stress, and loneliness were measured at baseline. SARS-CoV-2 infection and hospitalization due to COVID-19 was self-reported. Relative risks (RRs) were calculated by Poisson regression. RESULTS: 3663 participants reported a positive SARS-CoV-2 test (mean age = 55.0 years, standard deviation = 13.8) during follow-up. Among these participants, chronic depression prior to the pandemic [RR = 1.72; 95% confidence interval (CI) 1.20-2.46], and probable depression (RR = 1.81, 95% CI 1.08-3.03), being very worried about COVID-19 (RR = 1.79; 95% CI 1.12-2.86), and loneliness (RR = 1.81, 95% CI 1.02-3.20) reported at baseline were each associated with subsequent COVID-19 hospitalization, adjusting for demographic factors and healthcare worker status. Anxiety and perceived stress were not associated with hospitalization. Depression, worry about COVID-19, and loneliness were as strongly associated with hospitalization as were high cholesterol and hypertension, established risk factors for COVID-19 severity. CONCLUSIONS: Psychological distress may be a risk factor for hospitalization in patients with SARS-CoV-2 infection. Assessment of psychological distress may identify patients at greater risk of hospitalization. Future work should examine whether addressing distress improves physical health outcomes.

Epigenetic aging and PTSD outcomes in the immediate aftermath of trauma.

BACKGROUND: Psychological trauma exposure and posttraumatic stress disorder (PTSD) have been associated with advanced epigenetic age. However, whether epigenetic aging measured at the time of trauma predicts the subsequent development of PTSD outcomes is unknown. Moreover, the neural substrates underlying posttraumatic outcomes associated with epigenetic aging are unclear. METHODS: We examined a multi-ancestry cohort of women and men (n = 289) who presented to the emergency department (ED) after trauma. Blood DNA was collected at ED presentation, and EPIC DNA methylation arrays were used to assess four widely used metrics of epigenetic aging (HorvathAge, HannumAge, PhenoAge, and GrimAge). PTSD symptoms were evaluated longitudinally at the time of ED presentation and over the ensuing 6 months. Structural and functional neuroimaging was performed 2 weeks after trauma. RESULTS: After covariate adjustment and correction for multiple comparisons, advanced ED GrimAge predicted increased risk for 6-month probable PTSD diagnosis. Secondary analyses suggested that the prediction of PTSD by GrimAge was driven by worse trajectories for intrusive memories and nightmares. Advanced ED GrimAge was also associated with reduced volume of the whole amygdala and specific amygdala subregions, including the cortico-amygdaloid transition and the cortical and accessory basal nuclei. CONCLUSIONS: Our findings shed new light on the relation between biological aging and trauma-related phenotypes, suggesting that GrimAge measured at the time of trauma predicts PTSD trajectories and is associated with relevant brain alterations. Furthering these findings has the potential to enhance early prevention and treatment of posttraumatic psychiatric sequelae.

Psychometric properties of the mini international neuropsychiatric interview (MINI) psychosis module: a Sub-Saharan Africa cross country comparison.

BACKGROUND: The Mini International Neuropsychiatric Inventory 7.0.2 (MINI-7) is a widely used tool and known to have sound psychometric properties; but very little is known about its use in low and middle-income countries (LMICs). This study aimed to examine the psychometric properties of the MINI-7 psychosis items in a sample of 8609 participants across four countries in Sub-Saharan Africa. METHODS: We examined the latent factor structure and the item difficulty of the MINI-7 psychosis items in the full sample and across four countries. RESULTS: Multiple group confirmatory factor analyses (CFAs) revealed an adequate fitting unidimensional model for the full sample; however, single group CFAs at the country level revealed that the underlying latent structure of psychosis was not invariant. Specifically, although the unidimensional structure was an adequate model fit for Ethiopia, Kenya, and South Africa, it was a poor fit for Uganda. Instead, a 2-factor latent structure of the MINI-7 psychosis items provided the optimal fit for Uganda. Examination of item difficulties revealed that MINI-7 item K7, measuring visual hallucinations, had the lowest difficulty across the four countries. In contrast, the items with the highest difficulty were different across the four countries, suggesting that MINI-7 items that are the most predictive of being high on the latent factor of psychosis are different for each country. CONCLUSIONS: The present study is the first to provide evidence that the factor structure and item functioning of the MINI-7 psychosis vary across different settings and populations in Africa.

The emerging role of the gut microbiome in posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) occurs in some people following exposure to a terrifying or catastrophic event involving actual/threatened death, serious injury, or sexual violence. PTSD is a common and debilitating mental disorder that imposes a significant burden on individuals, their families, health services, and society. Moreover, PTSD is a risk factor for chronic diseases such as coronary heart disease, stroke, diabetes, as well as premature mortality. Furthermore, PTSD is associated with dysregulated immune function. Despite the high prevalence of PTSD, the mechanisms underlying its etiology and manifestations remain poorly understood. Compelling evidence indicates that the human gut microbiome, a complex community of microorganisms living in the gastrointestinal tract, plays a crucial role in the development and function of the host nervous system, complex behaviors, and brain circuits. The gut microbiome may contribute to PTSD by influencing inflammation, stress responses, and neurotransmitter signaling, while bidirectional communication between the gut and brain involves mechanisms such as microbial metabolites, immune system activation, and the vagus nerve. In this literature review, we summarize recent findings on the role of the gut microbiome in PTSD in both human and animal studies. We discuss the methodological limitations of existing studies and suggest future research directions to further understand the role of the gut microbiome in PTSD.

The link between post-traumatic stress disorder and systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a heterogeneous, multisystem autoimmune disorder characterized by unpredictable disease flares. Although the pathogenesis of SLE is complex, an epidemiologic link between posttraumatic stress disorder (PTSD) and the development of SLE has been identified, suggesting that stress-related disorders alter the susceptibility to SLE. Despite the strong epidemiologic evidence connecting PTSD and SLE, gaps remain in our understanding of how the two may be connected. Perturbations in the autonomic nervous system, neuroendocrine system, and at the genomic level may cause and sustain immune dysregulation that could lower the threshold for the development and propagation of SLE. We first describe shared risk factors for SLE and PTSD. We then describe potential biological pathways which may facilitate excessive inflammation in the context of PTSD. Among those genetically predisposed to SLE, systemic inflammation that accompanies chronic stress may fan the flames of smoldering SLE by priming immune pathways. Further studies on the connection between trauma and inflammation will provide important data on pathogenesis, risk factors, and novel treatments for SLE.

Integrating human brain proteomes with genome-wide association data implicates novel proteins in post-traumatic stress disorder.

Genome-wide association studies (GWAS) have identified several risk loci for post-traumatic stress disorder (PTSD); however, how they confer PTSD risk remains unclear. We aimed to identify genes that confer PTSD risk through their effects on brain protein abundance to provide new insights into PTSD pathogenesis. To that end, we integrated human brain proteomes with PTSD GWAS results to perform a proteome-wide association study (PWAS) of PTSD, followed by Mendelian randomization, using a discovery and confirmatory study design. Brain proteomes (N = 525) were profiled from the dorsolateral prefrontal cortex using mass spectrometry. The Million Veteran Program (MVP) PTSD GWAS (n = 186,689) was used for the discovery PWAS, and the Psychiatric Genomics Consortium PTSD GWAS (n = 174,659) was used for the confirmatory PWAS. To understand whether genes identified at the protein-level were also evident at the transcript-level, we performed a transcriptome-wide association study (TWAS) using human brain transcriptomes (N = 888) and the MVP PTSD GWAS results. We identified 11 genes that contribute to PTSD pathogenesis via their respective cis-regulated brain protein abundance. Seven of 11 genes (64%) replicated in the confirmatory PWAS and 4 of 11 also had their cis-regulated brain mRNA levels associated with PTSD. High confidence level was assigned to 9 of 11 genes after considering evidence from the confirmatory PWAS and TWAS. Most of the identified genes are expressed in other PTSD-relevant brain regions and several are preferentially expressed in excitatory neurons, astrocytes, and oligodendrocyte precursor cells. These genes are novel, promising targets for mechanistic and therapeutic studies to find new treatments for PTSD.

Using phenotype risk scores to enhance gene discovery for generalized anxiety disorder and posttraumatic stress disorder.

UK Biobank (UKB) is a key contributor in mental health genome-wide association studies (GWAS) but only ~31% of participants completed the Mental Health Questionnaire ("MHQ responders"). We predicted generalized anxiety disorder (GAD), posttraumatic stress disorder (PTSD), and major depression symptoms using elastic net regression in the ~69% of UKB participants lacking MHQ data ("MHQ non-responders"; NTraining = 50%; NTest = 50%), maximizing the informative sample for these traits. MHQ responders were more likely to be female, from higher socioeconomic positions, and less anxious than non-responders. Genetic correlation of GAD and PTSD between MHQ responders and non-responders ranged from 0.636 to 1.08; both were predicted by polygenic scores generated from independent cohorts. In meta-analyses of GAD (N = 489,579) and PTSD (N = 497,803), we discovered many novel genomic risk loci (13 for GAD and 40 for PTSD). Transcriptomic analyses converged on altered regulation of prenatal dorsolateral prefrontal cortex in these disorders. Our results provide one roadmap by which sample size and statistical power may be improved for gene discovery of incompletely ascertained traits in the UKB and other biobanks with limited mental health assessment.

Genetically regulated multi-omics study for symptom clusters of posttraumatic stress disorder highlights pleiotropy with hematologic and cardio-metabolic traits.

Posttraumatic stress disorder (PTSD) is a psychiatric disorder that may arise in response to severe traumatic event and is diagnosed based on three main symptom clusters (reexperiencing, avoidance, and hyperarousal) per the Diagnostic Manual of Mental Disorders (version DSM-IV-TR). In this study, we characterized the biological heterogeneity of PTSD symptom clusters by performing a multi-omics investigation integrating genetically regulated gene, splicing, and protein expression in dorsolateral prefrontal cortex tissue within a sample of US veterans enrolled in the Million Veteran Program (N total = 186,689). We identified 30 genes in 19 regions across the three PTSD symptom clusters. We found nine genes to have cell-type specific expression, and over-representation of miRNA-families - miR-148, 30, and 8. Gene-drug target prioritization approach highlighted cyclooxygenase and acetylcholine compounds. Next, we tested molecular-profile based phenome-wide impact of identified genes with respect to 1678 phenotypes derived from the Electronic Health Records of the Vanderbilt University biorepository (N = 70,439). Lastly, we tested for local genetic correlation across PTSD symptom clusters which highlighted metabolic (e.g., obesity, diabetes, vascular health) and laboratory traits (e.g., neutrophil, eosinophil, tau protein, creatinine kinase). Overall, this study finds comprehensive genomic evidence including clinical and regulatory profiles between PTSD, hematologic and cardiometabolic traits, that support comorbidities observed in epidemiologic studies of PTSD.