Single-cell multiomics of neuron activation reveals context-specific genetics of brain disorders
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–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.
Article Details
Journal Info
Science
American Association for the Advancement of Science
Authors (21)
Lifan Liang
Department of Human Genetics, The University of Chicago, Chicago, IL, USA.
Siwei Zhang
Zicheng Wang
Department of Human Genetics, The University of Chicago, Chicago, IL, USA.
Hanwen Zhang
Chuxuan Li
Center for Psychiatric Genetics, Endeavor Health Research Institute, Evanston, IL, USA.
Christina Thapa
Emily K. Oh
Center for Psychiatric Genetics, Endeavor Health Research Institute, Evanston, IL, USA.
David Sirkin
Center for Psychiatric Genetics, Endeavor Health Research Institute, Evanston, IL, USA.
Xiaotong Sun
Alexandra Barishman
Center for Psychiatric Genetics, Endeavor Health Research Institute, Evanston, IL, USA.
Ada McCarroll
Center for Psychiatric Genetics, Endeavor Health Research Institute, Evanston, IL, USA.
Alexandra C. Duhe
Center for Psychiatric Genetics, Endeavor Health Research Institute, Evanston, IL, USA.
Sheng Qian
Department of Human Genetics, The University of Chicago, Chicago, IL, USA.
Xiaoyuan Zhong
Department of Human Genetics, The University of Chicago, Chicago, IL, USA.
Brendan Jamison
Whitney Wood
Center for Psychiatric Genetics, Endeavor Health Research Institute, Evanston, IL, USA.
Alena Kozlova
Zhiping P. Pang
Alan R. Sanders
Xin He
Jubao Duan