Single-cell multiomics of neuron activation reveals context-specific genetics of brain disorders
- Lifan Liang
- Siwei Zhang
- Zicheng Wang
- Hanwen Zhang
- Chuxuan Li
- Christina Thapa
- Emily K. 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
2026-06-25
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.