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

Abstract

Post-traumatic stress disorder (PTSD) is a debilitating psychiatric condition occurring in individuals exposed to trauma. The study of PTSD is complicated by highly heterogeneous presentations and experiences of trauma.Here, we studied genetic correlates of PTSD and resilience among a group of responders to the World Trade Center (WTC) 9/11/2001 attacks. This cohort represents a unique opportunity to study genetic risk factors for PTSD, and resilience, following a single, shared, well-documented trauma. We calculated polygenic risk scores associated with PTSD among these 375 individuals, and demonstrated a significant genetic association with social cognition traits, brain volumetric phenotypes, and PTSD-GWAS-derived PRS.Our results demonstrate significant genetic regulation of PTSD severity (CAPS scores) and chronicity (past-month CAPS). PRS derived from GWAS of ADHD, ASD, and brain imaging phenotypes (Amygdala and Putamen volume) were associated with multiple PTSD traits in this study. Interestingly, we find greater genetic contribution to PTSD among cases compared to our full cohort. In addition, we tested for associations between exposures to traumatic stressors, including WTC-related exposures, childhood trauma, and traumatic life events since 9/11. Together, polygenic risk and exposures to traumatic stress explain ∼45% of variance in lifetime CAPS among the full cohort (R2=0.454), and ∼48% of variance in past-month CAPS (R2=0.480). These participants represent a highly vulnerable population, with exposures to severe trauma during 9/11 and the following days. Identifying individuals at heightened risk for PTSD, or who may be suited to particular therapies, is of special importance and relevance in this group. In particular, the identification of MRI imaging phenotypes indicates that coupling of neuroimaging with genetic risk score calculations may predict PTSD outcomes.

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

“…Moreover, an increasing amount of direct brain imaging [48][49][50] and recent genomic analyses implicate specific subtypes of inhibitory GABAergic neurons in PTSD 27,51 . Transcriptome-wide association studies using PTSD GWAS 52 , as well as two independent transcriptomic studies of PM brain tissue from PTSD cases and controls 27,51 , associated GABAergic signaling with PTSD risk and illness state. This suggests that decreases in GABAergic activity confer susceptibility to traumatic stress and may be involved in the pathophysiology of PTSD 17 .…”

“…Nonetheless, it would be an oversimplification to speculate that glucocorticoid response in hiPSC-derived neurons represents the 'pretrauma state' , and that analyses of patient PBMCs and brain tissue reflect the 'post-trauma state' . Stress impacts risk to psychiatric disorders throughout the lifespan-across prenatal development 62,63 , childhood 52 and adulthood 52,64,65 . Moreover, the significant and positive relationship between our observed associations in NGN2-neurons and previously demonstrated transcriptional PTSD signatures in PM brains suggests that some impacts of glucocorticoid exposure may persist through to adulthood.…”

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

“…Data on 10 WTC-related exposures 19 (e.g., exposed to human remains, received treatment for an illness/injury during WTC recovery work) was obtained from interviews and self-report questionnaires completed by participants during their first health-monitoring visit to the WTC-HP, an average of 4.3 (SD=2.7) years following 9/11/2001. In-person clinical assessments were conducted an average of 13 (SD=2.3) years following 9/11/2011.…”

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

“…The genetic etiology of PTSD varies according to gender [6][7][8] , and index trauma type [9][10][11] ; consequently, studies that examine relatively homogeneous cohorts -i.e. individuals exposed to only one specific type of trauma [12][13][14][15][16][17][18] -have identified genome-wide significant associations that…”