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

Abstract

Despite experiencing a significant trauma, only a subset of World Trade Center (WTC) rescue and recovery workers developed posttraumatic stress disorder (PTSD). Identification of biomarkers is critical to the development of targeted interventions for treating disaster responders and potentially preventing the development of PTSD in this population. Analysis of gene expression from these individuals can help in identifying biomarkers of PTSD. We established a well-phenotyped sample of 371 WTC responders, recruited from a longitudinal WTC responder cohort, by obtaining blood, self-reported and clinical interview data. Using bulk RNA-sequencing from whole blood, we examined the association between gene expression and WTC-related PTSD symptom severity on (i) highest lifetime Clinician-Administered PTSD Scale (CAPS) score, (ii) past-month CAPS score, and (iii) PTSD symptom dimensions using a 5-factor model of re-experiencing, avoidance, emotional numbing, dysphoric arousal and anxious arousal symptoms. We corrected for sex, age, genotype-derived principal components and surrogate variables. Finally, we performed a meta-analysis with existing PTSD studies (total N=1,016), using case/control status as the predictor and correcting for these variables. We identified 66 genes significantly associated with highest lifetime CAPS score (FDR-corrected p<0.05), and 31 genes associated with past-month CAPS. Our more granular analyses of PTSD symptom dimensions identified additional genes that did not reach statistical significance in our overall analysis. In particular, we identified 82 genes significantly associated with lifetime anxious arousal symptoms. Several genes significantly associated with multiple PTSD symptom dimensions and lifetime CAPS score (SERPINA1, RPS6KA1, and STAT3) have been previously associated with PTSD. Geneset enrichment of these findings has identified pathways significant in metabolism, immune signaling, other psychiatric disorders, neurological signaling, and cellular structure. Our meta-analysis revealed 10 genes that reached genome-wide significance, all of which were down-regulated in cases compared to controls (CIRBP, TMSB10, FCGRT, CLIC1, RPS6KB2, HNRNPUL1, ALDOA, NACA, ZNF429 and COPE). Additionally, cellular deconvolution highlighted an enrichment in CD4 T cells and eosinophils in responders with PTSD compared to controls. The distinction in significant genes between lifetime CAPS score and the anxious arousal symptom dimension of PTSD highlights a potential biological difference in the mechanism underlying the heterogeneity of the PTSD phenotype. Future studies should be clear about methods used to analyze PTSD status, as phenotypes based on PTSD symptom dimensions may yield different gene sets than combined CAPS score analysis. Potential biomarkers implicated from our meta-analysis may help improve therapeutic target development for PTSD.

Modeling gene × environment interactions in PTSD using human neurons reveals diagnosis-specific glucocorticoid-induced gene expression

“…To identify upstream drivers of the PTSD-specific HCort response signature, enrichment for TF targets, defined based on MSigDB C3 gene set groupings 113 , was performed using the FUMA pipeline 114 . TFs were tested for their overlap with genes previously reported in PM brains 27 of individuals with PTSD and genes associated with CAPS scores in whole blood 115 . The significance of the number of TFs enriched in PTSD gene sets was tested using a binomial test.…”

Mapping anorexia nervosa genes to clinical phenotypes

“…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 ).…”

Polygenic regulation of PTSD severity and outcomes among World Trade Center responders

“…Here, we characterized a unique sample of 371 WTC responders of diverse backgrounds and training, all exposed to the aftermath of the 9/11 terrorist attacks, recruited on average 13.5 years after 9/11/2001 and ranging in PTSD symptom severity from no/low symptoms to severe PTSD. The present study aimed to fill a major gap in our understanding of the development and chronicity of this disabling condition by conducting genome-wide genetic and gene expression profiling 11 in a representative sample of WTC responders, characterized in depth with in-person psychiatric, medical, and psychosocial assessments. The existence of this cohort represents a unique opportunity to study genetic risk factors for PTSD following a shared and well-documented trauma in a sample of individuals who nonetheless vary greatly in severity of exposures to WTC-related trauma and other lifetime traumas.…”