| Summary: | <p> Large scale genomic and transcriptomic analyses are illuminating the complex genetic nature of psychiatric disorders such as schizophrenia. Newly identified associations between genetic variations and disease risk must be functionally validated, in order to understand the underlying cellular and molecular mechanism contributing to disease. A scalable, robust platform for modeling the effects that such myriad perturbations might have on neural systems is necessary. Here, we combine human induced pluripotent stem cells, cerebral organoid differentiations, and a catalytically inactivated endonuclease dCas9 fused to the KRAB transcriptional repressor. We further demonstrate the feasibility of, and important considerations associated with, developing such a platform, by applying it to study the effects of perturbing <i>FURIN,</i> a gene with an expression quantitative trait locus significantly associated with schizophrenia. Our data demonstrate the utility and scalability of this system for manipulating disease-associated gene expression in order to query cellular phenotypic effect.</p><p>
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