单细胞 RNA 测序鉴定小鼠多巴胺能神经元中的候选基因用于散发性帕金森病的研究。
Single-Cell RNA-Seq of Mouse Dopaminergic Neurons Informs Candidate Gene Selection for Sporadic Parkinson Disease.
机构信息
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, UK.
出版信息
Am J Hum Genet. 2018 Mar 1;102(3):427-446. doi: 10.1016/j.ajhg.2018.02.001.
Genetic variation modulating risk of sporadic Parkinson disease (PD) has been primarily explored through genome-wide association studies (GWASs). However, like many other common genetic diseases, the impacted genes remain largely unknown. Here, we used single-cell RNA-seq to characterize dopaminergic (DA) neuron populations in the mouse brain at embryonic and early postnatal time points. These data facilitated unbiased identification of DA neuron subpopulations through their unique transcriptional profiles, including a postnatal neuroblast population and substantia nigra (SN) DA neurons. We use these population-specific data to develop a scoring system to prioritize candidate genes in all 49 GWAS intervals implicated in PD risk, including genes with known PD associations and many with extensive supporting literature. As proof of principle, we confirm that the nigrostriatal pathway is compromised in Cplx1-null mice. Ultimately, this systematic approach establishes biologically pertinent candidates and testable hypotheses for sporadic PD, informing a new era of PD genetic research.
通过全基因组关联研究（GWAS）主要探索了调节散发性帕金森病（PD）风险的遗传变异。然而，与许多其他常见的遗传疾病一样，受影响的基因在很大程度上仍然未知。在这里，我们使用单细胞 RNA-seq 来描述胚胎期和出生后早期小鼠大脑中的多巴胺能（DA）神经元群体。这些数据通过其独特的转录谱，包括出生后神经母细胞群体和黑质（SN）DA 神经元，促进了对 DA 神经元亚群的无偏识别。我们使用这些群体特异性数据来开发一个评分系统，对所有 49 个与 PD 风险相关的 GWAS 区间中的候选基因进行优先级排序，包括已知与 PD 相关的基因和许多具有广泛支持文献的基因。作为原理验证，我们证实 Cplx1 缺失小鼠的黑质纹状体通路受损。最终，这种系统方法为散发性 PD 确定了具有生物学相关性的候选基因和可测试的假设，为 PD 遗传研究开辟了一个新时代。
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