Mitotic Instability and Clonal Hematopoiesis-Like Mechanisms Contribute to Schizophrenia Polygenic Risk

Background: Schizophrenia exhibits high heritability yet marked clinical heterogeneity and incomplete penetrance. Although polygenic risk primarily implicates synaptic and immune pathways, emerging evidence of elevated somatic mosaicism in patient brains suggests contributions from genomic instability. We tested whether common variants in genes predisposing to mosaic chromosomal alterations (mCAs), mitotic stress, and clonal hematopoiesis influence schizophrenia liability. Methods: Using European-ancestry summary statistics from the Psychiatric Genomics Consortium wave 3 GWAS (58,749 effective sample size), we conducted gene-based association testing (MAGMA), partitioned heritability estimation (LDSC), and transcriptome-wide association studies (TWAS with GTEx v8 MASHR models across six brain tissues). Five hypothesis-driven gene sets (mCA-related, mitotic stress, clonal hematopoiesis; plus housekeeping and monoaminergic controls) were curated, allowing overlaps to reflect biological convergence. Results: Small mCA-related (37 genes) and mitotic stress (43 genes) sets showed robust partitioned heritability enrichment (2.00-fold and 2.10-fold LD-adjusted, respectively; one-tailed p = 2.16 × 10⁻⁸ and 2.43 × 10⁻¹⁰, both Bonferroni-significant). Convergent individual signals emerged for PPP1R16B (MAGMA Z = 8.60; TWAS Z = +7.88 hippocampus) and MAD1L1 (MAGMA Z = 8.12), with positive regulatory directionality predominating. Clonal hematopoiesis overlap loci drove much of the signal, while control sets remained null. Conclusions: These findings support a supplementary etiological model whereby germline predisposition to mitotic instability and clonal-like expansion fosters low-level neuronal mosaicism, acting as a stochastic modifier atop polygenic risk to shape schizophrenia's heterogeneous presentation. This framework bridges blood-derived clonal hematopoiesis concepts with neurodevelopmental vulnerability, warranting integrated germline-somatic studies.