Single-cell multi-omics of cerebellar dysregulation in schizophrenia and bipolar disorder

项目摘要 神经精神障碍，如精神分裂症（SCZ）和双相情感障碍（BD）代表了大量的公众 健康负担。疾病相关基因和基因网络的识别一直被视为一个 最有前途的新疗法的一部分近几年来，在这方面取得了很大进展。 这些疾病相关基因的发现，通过转录组学和表观基因组学研究死后， 脑组织然而，虽然SCZ和BD与多个细胞的结构和功能变化有关， 皮质和皮质下的大脑区域，大规模的基因组研究几乎完全集中在一个小的 新皮质区的数量。几条证据支持小脑在SCZ中的重要作用， BD，包括脑成像研究、解剖学研究和基因表达谱研究的结果， 在动物模型中证实了小脑在情绪状态和认知调节中的重要作用。 在这里，我们将进行单核RNA测序和单核染色质可及性分析， 描述SCZ和BD与细胞类型特异性转录组学和表观基因组学变化的相关性， 小脑（SCZ、BD和非疾病对照组各n=25）。使用这些数据，我们将执行系统 遗传学分析预测小脑中的“会聚神经科学”机制，将SNP与基因联系起来 到细胞类型到大脑结构和功能到精神病诊断。

Project Summary Neuropsychiatric disorders such as schizophrenia (SCZ) and bipolar disorder (BD) represent a substantial public health burden. The identification of disease-associated genes and gene networks has long been viewed as one of the most promising paths toward new therapies. In recent years, substantial progress has been made toward the discovery of these disease-associated genes through transcriptomic and epigenomic studies of post-mortem brain tissue. However, while SCZ and BD are associated with structural and functional changes in multiple cortical and sub-cortical brain regions, large-scale genomic studies have focused almost exclusively on a small number of neocortical areas. Several lines of evidence support an important role for the cerebellum in SCZ and BD, including results from brain imaging studies, anatomical studies, and gene expression profiling, and studies in animal models confirm important roles for the cerebellum in the regulation of emotional states and cognition. Here, we will perform single-nucleus RNA sequencing and single-nucleus chromatin accessibility assays to characterize associations of SCZ and BD with cell type-specific transcriptomic and epigenomic changes in the cerebellum (n=25 each for SCZ, BD, and non-diseased controls). Using these data, we will perform systems genetics analyses to predict “convergent neuroscience” mechanisms in the cerebellum, linking SNPs to genes to cell types to brain structure and function to psychiatric diagnoses.