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bioRxiv · 10.1101/2025.02.17.638682

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

Liang, L.·Zhang, S.·Wang, Z.·Zhang, H.·Li, C.·Duhe, A. C.·Sun, X.·Zhong, X.·Kozlova, A.·Jamison, B.·Wood, W. G.·Pang, Z. P.·Sanders, A. R.·He, X.·Duan, J.
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Abstract

Most causal variants for neuropsychiatric disorders (NPD) remain unknown. A major hurdle is that disease variants may act in specific contexts, such as during neuronal activation, which is difficult to study in vivo at the population level. We profiled single-nucleus neuron-activation multiomics in human induced pluripotent stem cell (iPSC)-derived neurons from 100 donors, revealing the NPD-relevant transcriptomic/epigenomic landscape of neuronal activation. We identified abundant genetic variants associated with activity-dependent gene expression (eQTL) and chromatin accessibility (caQTL), the latter explaining larger proportions of NPD heritability. Integrating multiomic data with genome-wide association studies (GWAS) further revealed NPD risk variants and genes with effects detected only upon stimulation, such as activity-dependent cholesterol metabolism. Our work highlights the power of cell stimulation to reveal context-specific "hidden" genetic effects.

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Liang, L., Zhang, S., Wang, Z., Zhang, H., Li, C., Duhe, A. C., Sun, X., Zhong, X., Kozlova, A., Jamison, B., Wood, W. G., Pang, Z. P., Sanders, A. R., He, X., Duan, J.. 2025-02-18. Single-cell multiomics of neuronal activation reveals context-dependent genetic control of brain disorders. https://doi.org/10.1101/2025.02.17.638682

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