Genome-wide association studies have discovered hundreds of loci associated with complex brain disorders, but it remains unclear in which cell types these loci are active. Here we integrate genome-wide association study results with single-cell transcriptomic data from the entire mouse nervous system to systematically identify cell types underlying brain complex traits. We show that psychiatric disorders are predominantly associated with projecting excitatory and inhibitory neurons. Neurological diseases were associated with different cell types, which is consistent with other lines of evidence. Notably, Parkinson's disease was genetically associated not only with cholinergic and monoaminergic neurons (which include dopaminergic neurons) but also with enteric neurons and oligodendrocytes. Using post-mortem brain transcriptomic data, we confirmed alterations in these cells, even at the earliest stages of disease progression. Our study provides an important framework for understanding the cellular basis of complex brain maladies, and reveals an unexpected role of oligodendrocytes in Parkinson's disease.

中文翻译：

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对大脑复杂性状背后的细胞类型进行基因鉴定可以深入了解帕金森病的病因。


全基因组关联研究发现了数百个与复杂脑部疾病相关的基因座，但仍不清楚这些基因座在哪些细胞类型中活跃。在这里，我们将全基因组关联研究结果与整个小鼠神经系统的单细胞转录组数据相结合，以系统地识别大脑复杂性状背后的细胞类型。我们发现精神疾病主要与投射的兴奋性和抑制性神经元有关。神经系统疾病与不同的细胞类型相关，这与其他证据一致。值得注意的是，帕金森病不仅与胆碱能和单胺能神经元（包括多巴胺能神经元）有遗传相关性，而且与肠神经元和少突胶质细胞也有遗传相关性。利用死后脑转录组数据，我们证实了这些细胞的改变，即使是在疾病进展的最早阶段。我们的研究为理解复杂脑部疾病的细胞基础提供了一个重要的框架，并揭示了少突胶质细胞在帕金森病中意想不到的作用。