An in silico transcription factor perturbation simulator uncovers diverse genetic architectures of brain disorders

Determining mechanisms and developing treatments for brain disorders with complex genetic architectures remains a challenge. We developed TFdisc, an in silico transcription factor (TF) perturbation simulator that uses wild-type single-cell RNA sequencing data to emulate corresponding post-TF perturbations. TFdisc’s accuracy in reconstructing gene regulatory networks, identifying differentially expressed genes, and predicting alterations in cell identity and lineage differentiation post-TF perturbations was validated across multiple perturbation datasets.Applying TFdisc to brain disorder risk factors revealed distinct molecular and cellular mechanisms. Further simulation of multiple TF simultaneous perturbations uncovered a “jigsaw mechanism” for schizophrenia and a “monolithic mechanism” for autism spectrum disorder.