Convergent impact of schizophrenia risk genes

Schizophrenia is a highly heritable psychiatric disorder with a complex genetic risk architecture that reflects the additive impact of hundreds of risk variants. While many schizophrenia-associated risk variants are thought to regulate the expression of target genes in a cell-type-specific manner, the mechanisms by which the effect of these myriad variants combine to contribute to risk remain unclear. Here we apply a CRISPR-based approach to evaluate in parallel twelve schizophrenia eGenes (that encompass common variation) in human glutamatergic neurons. Querying the shared neuronal impacts across risk genes uncovers a convergent effect concentrated on pathways of brain development and synaptic signaling. Our analyses reveal shared and divergent downstream effects of these twelve genes, independent of their previously annotated biological roles. General convergence of gene expression increases with increasing polygenicity, while the specificity of convergence increases between functionally similar genes. Convergent networks show brain-region and developmental period-specific enrichments, as well as disorder-specific enrichments for both rare and common variant target genes across schizophrenia, bipolar disorder, autism spectrum disorder, and intellectual disability. These gene targets are drug-able and potentially represent novel points of therapeutic intervention. Convergent signatures are also resolved in the post-mortem brain. Overall, convergence suggests a model to explain how non-additive interactions arise between risk genes and may explain cross-disorder pleiotropy of genetic risk for psychiatric disorders.