From Pruning to Plaque: Schizophrenia Genetics Accelerates Vascular Pathology via Peripheral Immune Extension

Background: Schizophrenia confers a 2- to 3-fold elevated risk of cardiovascular mortality, predominantly through atherosclerosis, yet genome-wide genetic correlations with atherosclerotic traits are consistently weak. This paradox suggests indirect biological mediation rather than direct pleiotropy. We hypothesized that schizophrenia polygenic risk acts as a systemic modifier, extending neurodevelopmental immune-pruning dysregulation peripherally to amplify vascular inflammation and plaque instability—a "pruning-to-plaque" cascade—without substantial overlap in core cellular senescence pathways. Methods: We conducted multi-layered genetic analyses contrasting a coronary artery calcification proxy for atherosclerosis (N ≈ 7,400) with the PGC3 schizophrenia meta-analysis (N ≈ 59,000 effective). Approaches included MAGMA gene-based testing with competitive and differential gene-set enrichment, LD score regression for partitioned heritability and bivariate correlation, and S-PrediXcan transcriptome-wide associations in brain and cardiovascular tissues, focusing on curated sets for synaptic pruning, glutamatergic plasticity, cellular scarring, and hematopoietic drivers. Results: Bivariate genetic correlation was near-null (r_g ≈ −0.02, p = 0.48). Schizophrenia showed extreme vascular transcriptomic enrichment in pruning-related immune pathways (enrichment 1.21-fold, p = 8.48 × 10⁻¹⁰; 43 FDR-significant associations, led by complement/MHC loci) and glutamatergic signaling, without senescence signals. Atherosclerosis exhibited modest scarring enrichment dominated by senescence markers (e.g., CDKN2A/B), lacking reciprocal pruning biology. Asymmetric convergence on chronic stress responses, with schizophrenia emphasizing immune-calcium axes and atherosclerosis senescence, supported indirect mediation. Conclusions: Schizophrenia polygenic risk likely accelerates atherosclerosis through systemic spillover of immune-pruning dysregulation—a pruning-to-plaque cascade—rather than direct senescence overlap. This refined hypothesis reconciles persistent comorbidity with minimal common-variant sharing, implicating peripheral immune modulation as a novel target for cardiovascular risk reduction in schizophrenia.