Developmentally dynamic, non-convergent transcriptomic profiles in CNV models for schizophrenia risk

Abstract Schizophrenia is a complex psychiatric disorder with significant genetic and clinical heterogeneity. Although numerous rare copy number variations (CNVs) with high risk for schizophrenia have been identified, they show no obvious overlap in gene content or function. We hypothesized that the downstream effects of schizophrenia-associated CNVs converge on shared molecular pathways. To test this, we profiled the prefrontal cortex of five schizophrenia-associated CNV mouse models — 15q13.3del, 3q29del, 1q21.1del, 22q11.2del, and 16p11.2dup — using single-cell RNA sequencing across two developmental stages: adolescence and adulthood. From 292,943 high-quality single-cell transcriptomes, we identified distinct age- and cell type-specific patterns of differential gene expression and biological pathway perturbations in each model. Rather than converging on a shared molecular mechanism, each CNV affected unique cellular pathways in a developmentally dynamic manner. Notably, genes dysregulated in deep-layer corticothalamic projection neurons from 15q13.3del and 16p11.2dup models, and intratelencephalic neurons from adult 22q11.2del mice, showed enrichment for schizophrenia-SNP heritability. These results support a model in which rare CNVs contribute to schizophrenia genetic risk through developmentally dynamic, distinct pathways rather than through a shared molecular mechanism.