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

Lifan Liang; Siwei Zhang; Zicheng Wang; Hanwen Zhang; C Li; Christina Thapa; E. Oh; David Sirkin; Xiaotong Sun; Alexandra Barishman; Ada McCarroll; Alexandra C. Duhe; Sheng Qian; Xiaoyuan Zhong; Brendan Jamison; Whitney Wood; Alena Kozlova; Zhiping P. Pang; Alan R. Sanders; Xin He; Jubao Duan

doi:10.1126/science.adw3949

NeuroscienceScienceJun 25, 2026

Peer-reviewed journal article

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

Lifan Liang iD, Siwei Zhang iD, Zicheng Wang iD, Hanwen Zhang iD, C Li iD, Christina Thapa iD, E. Oh iD, David Sirkin iD, Xiaotong Sun iD, Alexandra Barishman iD, Ada McCarroll iD, Alexandra C. Duhe iD, Sheng Qian iD, Xiaoyuan Zhong iD, Brendan Jamison iD, Whitney Wood iD, Alena Kozlova iD, Zhiping P. Pang iD, Alan R. Sanders iD, Xin He iD, Jubao Duan iD

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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