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

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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.