Discovery and replication of blood-based proteomic signature of PTSD in 9/11 responders

Abstract

Proteomics provides an opportunity to develop biomarkers for the early detection and monitoring of post-traumatic stress disorder (PTSD). However, research to date has been limited by small sample sizes and a lack of replication. This study performed Olink Proseek Multiplex Platform profiling of 81 proteins involved in neurological processes in 936 responders to the 9/11 disaster (mean age at blood draw = 55.41 years (SD = 7.93), 94.1% white, all men). Bivariate correlations and elastic net regressions were used in a discovery subsample to identify concurrent associations between PTSD symptom severity and the profiled proteins, and to create a multiprotein composite score. In hold-out subsamples, nine bivariate associations between PTSD symptoms and differentially expressed proteins were replicated: SKR3, NCAN, BCAN, MSR1, PVR, TNFRSF21, DRAXIN, CLM6, and SCARB2 (|r| = 0.08–0.17, p < 0.05). There were three replicated bivariate associations between lifetime PTSD diagnosis and differentially expressed proteins: SKR3, SIGLEC, and CPM (OR = 1.38–1.50, p < 0.05). The multiprotein composite score retained 38 proteins, including 10/11 proteins that replicated in bivariate tests. The composite score was significantly associated with PTSD symptom severity (β = 0.27, p < 0.001) and PTSD diagnosis (OR = 1.60, 95% CI: 1.17–2.19, p = 0.003) in the hold-out subsample. Overall, these findings suggest that PTSD is characterized by altered expression of several proteins implicated in neurological processes. Replicated associations with TNFRSF21, CLM6, and PVR support the neuroinflammatory signature of PTSD. The multiprotein composite score substantially increased associations with PTSD symptom severity over individual proteins. If generalizable to other populations, the current findings may inform the development of PTSD biomarkers.

Glial suppression and post-traumatic stress disorder: A cross-sectional study of 1,520 world trade center responders

“…Yet, GFAP levels could be significantly reduced in individuals with other neuropathologies specifically because GFAP might be binding directly to the cerebrum thereby avoiding being sloughed into the blood ( Pereira et al, 2021 ). A prior study of WTC responders with PTSD and mild cognitive impairment found downregulation of markers of inter-neuronal damage (e.g., , Neurocan, and Brevican) among responders with PTSD that were thought to be downregulated because of their increased cerebral absorption ( Kuan et al, 2020 ; Waszczuk et al, 2023 ). Similarly, studies have noted that PTSD is associated with changes to glucocorticoid activation via activation of the FKBP5 gene ( Kuan et al, 2017 , 2019 ), a result that could downregulate glia ( Nichols et al, 2005 ).…”

Discovery of 95 PTSD loci provides insight into genetic architecture and neurobiology of trauma and stress-related disorders

“…The top-gene, KANSL1, was significant in all cell types. Given previously reported associations between blood-based protein levels and PTSD, 38,39 we performed protein quantitative trait loci (pQTL) SMR 36 analysis for PTSD using data from the UK Biobank Pharma Proteomics Project 40 (N=54,306 samples and N=1,209 proteins). We identified 16 genes within 9 loci whose protein levels were significantly associated with PTSD (p<0.05/1,209 and p HEIDI > 0.05) (Fig.…”