近日，美国Endeavor Health研究所
该研究团队对来自100个供体的人类诱导多能干细胞来源的神经元进行了单核神经元激活的多组学分析，揭示了神经元激活与NPD相关的转录组学和表观基因组学景观。小组发现了大量与活性依赖性基因表达和染色质可及性相关的遗传变异，后者解释了NPD遗传率的较大比例。将多组学数据与全基因组关联研究相结合，进一步揭示了NPD风险变异和仅在刺激时才检测到的基因，如活动依赖性胆固醇代谢。他们的工作突出了细胞刺激的力量，揭示了特定环境的“隐藏”遗传效应。
据了解，大多数神经精神疾病（NPD）的病因变异尚不清楚。一个主要的障碍是疾病变异可能在特定的环境中起作用，例如在神经元激活期间，这很难在种群水平上进行体内研究。
附：英文原文
Title: Single-cell multiomics of neuron activation reveals context-specific genetics of brain disorders
Author: 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
Issue&Volume: 2026-06-25
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.
DOI: adw3949
Source: https://www.science.org/doi/10.1126/science.adw3949