Altered gene expression and PTSD symptom dimensions in World Trade Center responders

Marchese, Shelby; Cancelmo, Leo; Diab, Olivia; Cahn, Leah; Aaronson, Cindy J.; Daskalakis, Nikolaos P.; Schaffer, Jamie; Horn, Sarah R.; Johnson, Jessica; Schechter, Clyde B.; Desarnaud, Frank; Bierer, Linda M.; Makotkine, Iouri; Flory, Janine D.; Crane, Michael; Moline, Jacqueline; Udasin, Iris; Harrison, Denise; Roussos, Panos; Charney, Dennis S.; Koenen, Karestan C.; Southwick, Steven M.; Yehuda, Rachel; Pietrzak, Robert H.; Huckins, Laura; Feder, Adriana

doi:10.1038/s41380-022-01457-2

Cited by 10 publications

(9 citation statements)

References 105 publications

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“…To our knowledge, our results include the first AN-association within the MHC locus ( CLIC1 , chloride intracellular 1), a region that has been associated with many other psychiatric (Ripke et al, 2014; Stahl et al, 2019) and autoimmune disorders. In particular, CLIC1 has previously been identified as associated with schizophrenia (The Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium, 2017), autism (The Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium, 2017), MDD (Zhu et al, 2019), post-traumatic stress disorder (Marchese et al, 2021), neuroticism (Baselmans et al, 2019) and depressive phenotypes (Baselmans et al, 2019). Importantly, CLIC1 variants have also been associated with complement component C4 and C3 protein levels in the blood (Yang et al, 2012), which through the complement cascade (Sekar et al, 2016) are involved in immunological functions of pathogen clearance and in synaptic pruning and neuronal connectivity (Stephan, Barres, & Stevens, 2012).…”

Section: Discussionmentioning

confidence: 99%

Mapping anorexia nervosa genes to clinical phenotypes

et al. 2022

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Background Anorexia nervosa (AN) is a psychiatric disorder with complex etiology, with a significant portion of disease risk imparted by genetics. Traditional genome-wide association studies (GWAS) produce principal evidence for the association of genetic variants with disease. Transcriptomic imputation (TI) allows for the translation of those variants into regulatory mechanisms, which can then be used to assess the functional outcome of genetically regulated gene expression (GReX) in a broader setting through the use of phenome-wide association studies (pheWASs) in large and diverse clinical biobank populations with electronic health record phenotypes. Methods Here, we applied TI using S-PrediXcan to translate the most recent PGC-ED AN GWAS findings into AN-GReX. For significant genes, we imputed AN-GReX in the Mount Sinai BioMe™ Biobank and performed pheWASs on over 2000 outcomes to test the clinical consequences of aberrant expression of these genes. We performed a secondary analysis to assess the impact of body mass index (BMI) and sex on AN-GReX clinical associations. Results Our S-PrediXcan analysis identified 53 genes associated with AN, including what is, to our knowledge, the first-genetic association of AN with the major histocompatibility complex. AN-GReX was associated with autoimmune, metabolic, and gastrointestinal diagnoses in our biobank cohort, as well as measures of cholesterol, medications, substance use, and pain. Additionally, our analyses showed moderation of AN-GReX associations with measures of cholesterol and substance use by BMI, and moderation of AN-GReX associations with celiac disease by sex. Conclusions Our BMI-stratified results provide potential avenues of functional mechanism for AN-genes to investigate further.

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Section: Discussionmentioning

confidence: 99%

Mapping anorexia nervosa genes to clinical phenotypes

et al. 2022

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“…Cumulative trauma burden was quantified by adding up instances of reported traumatic exposure, as previously defined [46][47][48] . Briefly, traumas included in this analysis included sexual abuse, physical abuse, neglect, witnessing trauma, combat or occupational traumas, assault, and natural disasters.…”

Section: Human Trauma-exposed Post-mortem Brain Cohortmentioning

confidence: 99%

Common genetic variation impacts stress response in the brain

Seah,

Signer,

Deans

et al. 2023

Preprint

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To explain why individuals exposed to identical stressors experience divergent clinical outcomes, we determine how molecular encoding of stress modifies genetic risk for brain disorders. Analysis of post-mortem brain (n=304) revealed 8557 stress-interactive expression quantitative trait loci (eQTLs) that dysregulate expression of 915 eGenes in response to stress, and lie in stress-related transcription factor binding sites. Response to stress is robust across experimental paradigms: up to 50% of stress-interactive eGenes validate in glucocorticoid treated hiPSC-derived neurons (n=39 donors). Stress-interactive eGenes show brain region- and cell type-specificity, and, in post-mortem brain, implicate glial and endothelial mechanisms. Stress dysregulates long-term expression of disorder risk genes in a genotype-dependent manner; stress-interactive transcriptomic imputation uncovered 139 novel genes conferring brain disorder risk only in the context of traumatic stress. Molecular stress-encoding explains individualized responses to traumatic stress; incorporating trauma into genomic studies of brain disorders is likely to improve diagnosis, prognosis, and drug discovery.Graphical Abstract

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“…A key motivator of our study was to investigate whether including trauma in our studies might more deeply elucidate the genetic architecture of PTSD 12 . Therefore, we conducted a GWAS within our sample, following PGC broad PTSD diagnostic definitions 7 , and refined our associations using FINEMAP.…”

Section: Gwas Meta-analysis Reveals Ptsd Snps That Interact With Tslesmentioning

confidence: 99%

“…The genetic etiology of PTSD varies according to gender 6–8 , and index trauma type 9–11 ; consequently, studies that examine relatively homogeneous cohorts – i.e. individuals exposed to only one specific type of trauma 12–18 – have identified genome-wide significant associations that have not yet been identified using meta-analytic approaches across trauma types. Reducing cohort heterogeneity by characterizing trauma is imperative to advancing PTSD genetic discovery.…”

Section: Introductionmentioning

confidence: 99%

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Disentangling the roles of trauma and genetics in psychiatric disorders using an Electronic Health Records-based approach

Marchese

Cuddleston

Seah

et al. 2022

Preprint

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Posttraumatic stress disorder (PTSD) requires an exposure to trauma for diagnosis by the DSM-V. Despite this, there is no documented linear relationship between degree of trauma and severity/chronicity of PTSD.To determine whether traumatic and stressful life events (TSLEs) collected from Electronic Health Records (EHR) interact with PTSD genetics to better define individual risk of developing PTSD. We collected trauma information from patient records in the Mount Sinai BioMe™ biobank population-based cohort and tested for associations with PTSD. We generated a TSLE risk score (TRS), tested its association with PTSD, and for interactions with a polygenic risk score (PRS) of PTSD and a GWAS of PTSD using our biobank population.We used the Mount Sinai BioMe™ biobank patient population of 31,704 individuals with matched genotype and EHR data, which has been enrolling patients since 2006. Patient enrollment in BioMe™ is unrestricted, resulting in high diversity. Our study includes 1,990 individuals with PTSD and 28,478 individuals without PTSD from the Mount Sinai BioMe™ biobank.A total of 1,990 individuals with PTSD and 28,478 controls were analyzed (average age 42-78 years, 58.7% women). We identified a total of 22 EHR-derived TSLEs that were associated with PTSD (β> 0.029, p<1.61×10−3). TSLEs interacted with each other to increase the risk of developing PTSD, with the most significant interaction between being female (as a proxy for experiencing sexism) and being HIV+ (β=0.013, p=8.9×10−11). PRS of PTSD and lead SNPS from GWAS interacted with TSLEs and our TRS to increase PTSD risk. In addition to TRS interactions, we found significant interactions between PTSD PRS and domestic violence, and sexual assault in European Americans (β>207.74, p<1.80×10−3). rs113282988 and rs189796944 variants reached genome-wide significance in interactions with TRS (β>0.056, p<9.04×10−9), and rs189796944 in an interaction with Physical Survival TSLEs (β>0.127, p<4×10−8).In conclusion, quantification of trauma type, severity, and magnitude—alone and in concert with genetics—provides better prediction of PTSD risk than PRS alone. Understanding who is at risk of developing PTSD allows for timely clinical intervention and possible prevention.

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Altered gene expression and PTSD symptom dimensions in World Trade Center responders

Abstract: doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

Cited by 10 publications

References 105 publications

Mapping anorexia nervosa genes to clinical phenotypes

Mapping anorexia nervosa genes to clinical phenotypes

Common genetic variation impacts stress response in the brain

Disentangling the roles of trauma and genetics in psychiatric disorders using an Electronic Health Records-based approach

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