Polycomb-Derived Posttraumatic Stress Disorder (PTSD) Signals Diverge From Classical Aging Pathways and Converge on...

Background Posttraumatic stress disorder (PTSD) is a trauma- and stressor-related disorder characterized by persistent intrusion symptoms, avoidance, negative alterations in cognition and mood, and alterations in arousal and reactivity after exposure to a qualifying traumatic event. Symptoms must persist for more than one month and cause clinically significant distress or functional impairment under the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR) criteria. Reported PTSD prevalence in older adults varies according to diagnostic criteria and sampling frame; nationally representative studies have reported lifetime prevalence estimates of approximately 4.5% under the DSM-IV criteria and higher probable DSM-5 estimates when functional impairment was not included. Aging-related gene-set annotations may therefore provide one way to investigate biological vulnerability without directly measuring aging phenotypes. This secondary gene-set analysis tested whether supplied Polycomb-derived aging modules were competitively enriched in PTSD transcriptome-wide association study (TWAS) signals and whether their strongest gene-level signals were distinct from the curated GenAge human aging comparator. The post-hoc analyses were exploratory and hypothesis-generating. Methods PTSD S-PrediXcan/TWAS summary files were analyzed using absolute meta-Z-score ranking. Competitive gene set enrichment analysis (GSEA) used 2,000 gene-label permutations, and over-representation analysis (ORA) examined genes with absolute Z-scores greater than 3. Leading-edge overlap, signed directionality, top-gene comparisons, manual functional categorization, and sensitivity analyses after removing GenAge-overlapping genes were performed as secondary analyses. Results At the set level, GenAge showed the highest normalized enrichment score (NES = 1.0971; permutation p = 0.124938), while Module B was the strongest Polycomb-derived module but did not exceed GenAge (NES = 1.0474; p = 0.206397; false discovery rate (FDR) = 0.825588). None of the Polycomb-derived modules reached significance after FDR correction, and their ORA results were non-significant. Exploratory analysis of Module B showed larger top-tail absolute TWAS Z-scores than GenAge among the available top-50 output (median |Z|, 4.7845 versus 3.8822; nominal Mann-Whitney U p = 0.000474). Immune/major histocompatibility complex (MHC)/co-stimulation genes had the most negative descriptive mean Z-score, but no leading-edge or top-gene sign test showed statistically significant directional skew. Module B shared little leading-edge or top-gene overlap with GenAge. Conclusions Primary analyses did not demonstrate robust competitive enrichment of Polycomb-derived aging modules in PTSD TWAS. The Module B findings are secondary and exploratory. They generate a testable hypothesis that selected immune/MHC, adhesion, and membrane-signaling genes may contribute to PTSD vulnerability through a focal neuroimmune-adhesion interface that is partly separable from broad cellular aging programs. This possibility requires independent replication, formal pathway testing, and functional validation before mechanistic or translational conclusions can be drawn.