Single-cell multiomics of neuronal activation reveals context dependent genetic controls of brain disorders

Despite hundreds of genetic risk loci identified for neuropsychiatric disorders (NPD), most causal variants/genes remain unknown. A major hurdle is that disease risk variants may act in specific biological contexts, e.g., during neuronal activation, which is difficult to study in vivo at the population level. Here, we conducted a single-cell multiomics study of neuronal activation (stimulation) in human iPSC-induced excitatory and inhibitory neurons from 100 donors, and uncovered abundant neuronal stimulation-specific causal variants/genes for NPD. We surveyed NPD-relevant transcriptomic and epigenomic landscape of neuronal activation and identified thousands of genetic variants associated with activity-dependent gene expression (i.e., eQTL) and chromatin accessibility (i.e., caQTL). These caQTL explained considerably larger proportions of NPD heritability than the eQTL. Integrating the multiomic data with GWAS further revealed NPD risk variants/genes whose effects were only detected upon stimulation. Interestingly, multiple lines of evidence support a role of activity-dependent cholesterol metabolism in NPD. Our work highlights the power of cell stimulation to reveal context-dependent “hidden” genetic effects. This dataset aims to validate the cell type-specific transcriptomic effects of the key transcription factors (TFs) of the predicted autism-relevant gne regulatory networks (GRNs). Overall design: We introduce premature stop codons in TCF4, MEF2C, and RORB via cytosine base editing system with reporter editing enrichment, causing a permanent gene knockout (KO) in iPSCs. The iPSC-derived glutmatergic and GABAergic neurons were co-cultured with primary rat astrocytes and treated with KCl to model neuronal activity. Transcriptional effects of each TF KO were assayed by scRNA-seq.