Integrated MAGMA gene based and multi tissue transcriptome wide association analyses reveal locus specific genetic pleiotropy linking posttraumatic stress disorder to site specific cancer risk

Posttraumatic stress disorder (PTSD) develops in only a minority of trauma-exposed individuals, yet epidemiological studies have long noted complex, bidirectional links with cancer. Meta-analyses show no consistent overall elevation in cancer incidence (RR ≈ 1.05), but a robust and replicated increase for ovarian cancer (RR = 2.05), with signals often attenuating dramatically in sibling comparisons. The molecular mechanisms underlying this heterogeneity have remained unclear. We hypothesised that PTSD risk variants operate through locus-specific rather than diffuse pleiotropy. To test this, we applied MAGMA gene-based analysis to the largest European-ancestry PTSD GWAS (effective N = 638,463) and identified 235 genome-wide significant genes (Bonferroni p < 2.78 × 10⁻⁶), prominently including CTNND1, TRAIP, ZDHHC5, FOXP1, and POT1/PPP6C. We then performed S-PrediXcan transcriptome-wide association across 12 GTEx v8 tissues (139,299 gene–tissue pairs), followed by cross-tissue Stouffer meta-analysis and enrichment testing of 16 curated gene sets spanning telomere biology, DNA replication, antigen processing, EMT/Wnt signalling, senescence, and negative controls. The strongest pathway signal was REACTOME antigen processing and cross-presentation (1.19-fold enrichment, Mann–Whitney p = 3.19 × 10⁻³), peaking in ovary (mean |Z| = 1.29) with extreme downregulation of MICB (meta Z = − 19.87) and HLA-B (ovary Z = − 4.92). Cross-tissue meta-analysis revealed a compact set of master regulators: MICB, MDH2 (Z = + 19.20), BTN3A2, WNT3 (+ 18.62), FLOT1 (–17.24), and PPP6C (+ 15.35). Tissue patterns aligned precisely with epidemiology—strongest immune evasion and replication-stress signals in ovary, senescence escape and EMT in breast, telomere extension in lung, and combined immune/replication effects in colon. Negative controls showed only modest enrichment. These findings demonstrate that the same loci implicated in developmental synaptic and myelin pruning also create tissue-selective oncogenic vulnerabilities through immune evasion, telomere dysfunction, replication-stress tolerance, and mitochondrial reprogramming. The architecture elegantly reconciles strong ovarian risk, modest signals elsewhere, attenuation in sibling designs, and the heightened traumatic impact of cancer diagnoses. It extends the pruning-vulnerability cascade to systemic immunometabolic dysregulation and nominates high-priority targets (MICB/HLA pathways, POT1 regulation, MDH2, TRAIP) for stratified prevention and integrated psycho-oncology care.