From Developmental Mis-Pruning to Cardiac Senescence: A Mechanistic Cascade Explaining PTSD–AF Comorbidity Despite Near-Zero Genetic Correlation

Posttraumatic stress disorder (PTSD) is consistently linked to a higher risk of atrial fibrillation (AF), with large prospective cohorts showing roughly 13% increased incidence even after adjustment for demographics, lifestyle, and conventional cardiovascular risk factors [1]. Yet genome-wide analyses reveal almost no overall genetic correlation between the two conditions (rg ≈ 0.03) [2]. This discrepancy has long defied explanation under classical adult-onset models of PTSD. We hypothesized that the comorbidity arises through a developmental "pruning-vulnerability cascade": genetically driven excessive or mistimed synaptic and myelin pruning during adolescence (Phase 1) creates a latent, fragile neural scaffold; trauma unmasks this vulnerability, driving persistent plasticity failure, HPA-axis hyperactivity, and systemic inflammation (Phase 2); and prolonged stress accelerates cellular senescence that converges on atrial fibrosis and clinical AF (Phase 3).To test the model, we applied three orthogonal post-GWAS methods—MAGMA gene-set enrichment on the AF GWAS, comparative gene-set enrichment analysis between PTSD and AF, and tissue-swapped S-PrediXcan transcriptome-wide association studies—to European-ancestry summary statistics (PTSD: effective N = 638,463; AF: N ≈ 448,718) using 13 standardized public gene sets (GO, KEGG, Reactome, adult brain cell-type markers, HGNC HLA) plus negative controls. PTSD genetics projected onto cardiovascular tissues produced strong, specific enrichment in MHC/HLA (1.71-fold, p = 1.79 × 10⁻⁸), adult oligodendrocyte markers (1.33-fold, p = 1.28 × 10⁻⁴), complement cascade (1.27-fold, p = 4.54 × 10⁻⁴), and synaptic plasticity pathways, with coherent directional signals including C4A upregulation and PPP6C/POT1 changes. These signals were entirely absent or depleted when AF genetics were projected onto fear-relevant brain regions. In contrast, cellular senescence emerged as the leading pathway in AF MAGMA (nominal p = 0.019) and showed consistent overlap across both disorders, while NR3C1 reached genome-wide significance in AF analyses.These convergent, tissue-specific findings support the pruning-vulnerability cascade as the mechanistic bridge: upstream pruning signals are largely PTSD-specific (explaining low rg), while downstream senescence is shared and trauma-gated (explaining comorbidity). The model identifies trauma-exposed individuals with high HLA/C4A/oligodendrocyte polygenic scores as a high-risk subgroup for stratified prevention using complement modulators or senolytic agents. Broad multi-omic validation in diverse cohorts is now needed to translate this framework into clinical advances.