Abstract
There is a pressing need for in vitro experimental systems that allow for functional investigation of psychiatric disease biology. We developed an analytical framework that integrates genome-wide disease risk from GWAS with longitudinal in vitro gene expression profiles of human neuronal differentiation. We demonstrate that aggregate polygenic disease risk of specific psychiatric disorders is significantly associated with genes that are differentially expressed across neuronal differentiation. We find significant evidence for schizophrenia, which is driven by a longitudinal synaptic gene cluster that is upregulated during differentiation. Our findings reveal that in vitro neuronal differentiation can be used as an experimental model system to translate genetic findings to schizophrenia disease biology. Overall, this work emphasizes the use of longitudinal in vitro transcriptomic signatures as a cellular readout and the application to the genetics of complex traits.