85. SINGLE-CELL MULTIOMICS OF NEURONAL ACTIVATION REVEALS CONTEXT-DEPENDENT GENETIC EFFECTS ON BRAIN DISORDERS

Genome-wide association studies (GWAS) having identified hundreds of genetic risk loci for neurodevelopmental and neuropsychiatric disorders (NPD). Despite these successes, disease causal variants and genes remain largely unknown. A major hurdle is that brain disease risk variants may act in specific biological contexts, e.g., during neuronal activation in response to external stimuli like social experiences or stress. Neuronal activation regulates neurodevelopment and neuron plasticity. However, due to the inaccessibility of live brain, studying the effects of genetic variants in the context of neuron activation at the population level is immensely difficult, limiting our understanding of the genetics of NPD. Here, we modeled neuronal activation by using a neurodevelopmental model of co-cultured human iPSC-derived excitatory and inhibitory neurons from 100 donors. We generated an unprecedentedly large single-cell multiomics dataset for over a million neurons of 3 neuronal subtypes from the 100 donors at 3 neuronal activation (stimulation) time points (0, 1 and 6 hrs). We surveyed a landscape of activity-dependent transcriptomic and chromatin accessibility changes and identified transcription factors regulating cell-type-specific early and late neuronal responses. Leveraging the large iPSC cohort, we identified thousands of genetic variants associated with individual variation of gene expression and chromatin accessibility upon neuron activation, i.e., activity-dependent eQTL and caQTL (including allele-specific chromatin, ASoC) variants. These QTL are highly enriched (10-60 fold) for NPD genetic risk variants from GWAS. Integrative analyses of our mapped neuronal activity-dependent eQTL/caQTL with GWAS revealed abundant NPD risk genes/variants that only manifest functional effects upon neuronal activation (stimulation). Interestingly, multiple lines of evidence support a role of activity-dependent cholesterol metabolism in NPD. Our work provides mechanistic insights into cell-type-specific regulation of neuronal activation and expands the repertoire of context-specific causal variants/genes for NPD, highlighting the power of cell stimulation to reveal context-dependent “hidden” genetic effects.