Single-cell multiomics of neuron activation reveals context-specific genetics of brain disorders
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.
Authors
- E. Oh (ORCID: https://orcid.org/0009-0002-6317-4473)
- Zhiping P. Pang (ORCID: https://orcid.org/0000-0002-6183-1233)
- Alan R. Sanders (ORCID: https://orcid.org/0000-0001-6629-4011)
- Jubao Duan (ORCID: https://orcid.org/0000-0002-7215-3220)
- Brendan Jamison (ORCID: https://orcid.org/0000-0002-0208-9307)
- Alena Kozlova (ORCID: https://orcid.org/0000-0002-7298-7460)
- Xiaoyuan Zhong (ORCID: https://orcid.org/0000-0002-1948-6464)
- Xin He (ORCID: https://orcid.org/0000-0001-9011-5212)
- Lifan Liang (ORCID: https://orcid.org/0000-0002-2495-4779)
- C Li
- Sheng Qian (ORCID: https://orcid.org/0000-0003-4337-8532)
- Alexandra Barishman (ORCID: https://orcid.org/0009-0007-2801-290X)
- Ada McCarroll
- Alexandra Duhe
- Hanwen Zhang (ORCID: https://orcid.org/0000-0001-8490-918X)
- Zicheng Wang (ORCID: https://orcid.org/0000-0002-3646-7572)
- Siwei Zhang (ORCID: https://orcid.org/0000-0002-1646-063X)
- Christina Thapa (ORCID: https://orcid.org/0000-0003-0822-2911)
- Xiaotong Sun
- David Sirkin (ORCID: https://orcid.org/0009-0005-9985-1052)
- Whitney Wood (ORCID: https://orcid.org/0009-0007-3736-8078)
Institutions
- Johnson University (US)
- University of Chicago (US)
- Evanston Hospital (US)
- University of Pennsylvania (US)
Publication Details
- Journal
- Science
- Published
- 2026-06-25
- DOI
- https://doi.org/10.1126/science.adw3949
- Citations
- 1
- Primary Topic
- Single-cell and spatial transcriptomics
- Type
- article
- Field-Weighted Citation Impact
- 6.29
Funders
- National Institute on Aging
- National Heart, Lung, and Blood Institute
- National Institute of Mental Health
- National Institute of Allergy and Infectious Diseases