The MHC/Complement-Driven Pruning-to-Plaque Cascade: Genomic Evidence for Immune-Mediated Acceleration of Atherosclerosis in Schizophrenia

Individuals with schizophrenia die 15–20 years earlier than the general population, with cardiovascular disease accounting for 40–50% of deaths. Despite consistent epidemiological evidence of accelerated atherosclerosis—including mortality rate ratios of 2.80 for overall CVD and substantially elevated risks of coronary heart disease and stroke—the genome-wide genetic correlation with coronary artery disease is near zero. This dissociation has made the underlying mechanisms difficult to explain.We hypothesized that schizophrenia risk variants enhancing complement C4A-mediated synaptic pruning during brain development establish a persistent systemic pro-inflammatory tone that spills over into the vasculature, amplifying plaque formation and instability without initiating atherogenesis. We term this the MHC/Complement-Driven Pruning-to-Plaque Cascade.Using the PGC3 schizophrenia GWAS and a large coronary artery calcification GWAS, we conducted standardized multi-layered analyses: MAGMA competitive gene-set testing, LD-score partitioned heritability, and S-PrediXcan/TWAS across five cardiovascular GTEx v8 tissues (aorta, coronary artery, tibial artery, left ventricle, atrial appendage).Schizophrenia polygenic risk produced robust and highly specific enrichments in cardiovascular tissues: the HGNC Histocompatibility Complex showed 2.63-fold enrichment (p = 1.29 × 10⁻²⁰), with 15 of 18 testable HLA genes surviving FDR correction; the Reactome Complement Cascade was enriched 1.42-fold (p = 0.049), driven by extreme upregulation of C4A in atrial appendage (Z = 11.16, p ≈ 6 × 10⁻²⁹); synaptic plasticity pathways (1.25–1.36-fold) and clonal hematopoiesis genes (1.27-fold) were also significantly enriched. In clear contrast, classical atherosclerosis genetics were dominated by cellular senescence (CDKN2A/B) and adult astrocyte markers, with no MHC or pruning signals.These results demonstrate that neurodevelopmental immune-pruning alleles function as a systemic amplifier of vascular inflammation. The Pruning-to-Plaque Cascade reconciles the profound epidemiological burden with the genetic architecture and nominates complement modulation as a promising target for precision cardiovascular prevention in high-risk schizophrenia patients.