Science (New York, N.Y.) · 2026
Single-cell multiomics of neuron activation reveals context-specific genetics of brain disorders.
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Liang Lifan, Zhang Siwei, Wang Zicheng, Zhang Hanwen, Li Chuxuan, Thapa Christina, Oh Emily K, Sirkin David, Sun Xiaotong, Barishman Alexandra, McCarroll Ada, Duhe Alexandra C, Qian Sheng, Zhong Xiaoyuan, Jamison Brendan, Wood Whitney, Kozlova Alena, Pang Zhiping P, Sanders Alan R, He Xin, Duan Jubao
Аннотация
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-derived neurons from 100 donors, revealing the NPD-relevant transcriptomic and epigenomic landscape of neuronal activation. We identified abundant genetic variants associated with activity-dependent gene expression and chromatin accessibility, the latter explaining larger proportions of NPD heritability. Integrating multiomics data with genome-wide association studies 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.