Single-cell multiomics of neuron activation reveals context-specific genetics of brain disorders

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Abstract
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.
Funding Information
  • National Institutes of Health (R01MH116281)
  • National Institutes of Health (R01MH106575)
  • National Institutes of Health (RM1MH133065)
  • National Institutes of Health (R01MH106575)
  • National Institutes of Health (R01AG081374)
  • National Institutes of Health (R01MH110531)

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