Background The ganglionic eminences (GE) are fetal-specific structures that give rise to gamma-aminobutyric acid (GABA)- and acetylcholine-releasing neurons of the forebrain. Given the evidence for GABAergic, cholinergic, and neurodevelopmental disturbances in schizophrenia, we tested the potential involvement of GE neuron development in mediating genetic risk for the condition. Study Design We combined data from a recent large-scale genome-wide association study of schizophrenia with single-cell RNA sequencing data from the human GE to test the enrichment of schizophrenia risk variation in genes with high expression specificity for developing GE cell populations. We additionally performed the single nuclei Assay for Transposase-Accessible Chromatin with Sequencing (snATAC-Seq) to map potential regulatory genomic regions operating in individual cell populations of the human GE, using these to test for enrichment of schizophrenia common genetic variant liability and to functionally annotate non-coding variants-associated with the disorder. Study Results Schizophrenia common variant liability was enriched in genes with high expression specificity for developing neuron populations that are predicted to form dopamine D1 and D2 receptor-expressing GABAergic medium spiny neurons of the striatum, cortical somatostatin-positive GABAergic interneurons, calretinin-positive GABAergic neurons, and cholinergic neurons. Consistent with these findings, schizophrenia genetic risk was concentrated in predicted regulatory genomic sequence mapped in developing neuronal populations of the GE. Conclusions Our study implicates prenatal development of specific populations of GABAergic and cholinergic neurons in later susceptibility to schizophrenia, and provides a map of predicted regulatory genomic elements operating in cells of the GE.

中文翻译：

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产前 GABA 能和胆碱能神经元发育对精神分裂症易感性的遗传意义


背景 神经节隆起 (GE) 是胎儿特有的结构，可产生释放γ-氨基丁酸 (GABA) 和乙酰胆碱的前脑神经元。鉴于精神分裂症中 GABA 能、胆碱能和神经发育障碍的证据，我们测试了 GE 神经元发育在调节该疾病遗传风险中的潜在参与。研究设计我们将最近一项精神分裂症大规模全基因组关联研究的数据与来自人类 GE 的单细胞 RNA 测序数据相结合，以测试开发 GE 细胞群时具有高表达特异性的基因中精神分裂症风险变异的富集。我们还进行了转座酶可及染色质测序 (snATAC-Seq) 的单核测定，以绘制在人类 GE 的单个细胞群中运行的潜在调控基因组区域，使用这些区域来测试精神分裂症常见遗传变异倾向的富集并在功能上注释与疾病相关的非编码变体。研究结果 精神分裂症常见变异倾向富含对神经元群发育具有高表达特异性的基因，这些神经元群预计会形成纹状体表达多巴胺 D1 和 D2 受体的 GABA 能中型多棘神经元、皮质生长抑素阳性 GABA 能中间神经元、钙视网膜素阳性 GABA 能神经元和胆碱能神经元。与这些发现一致，精神分裂症遗传风险集中在 GE 发育神经元群中绘制的预测调控基因组序列。 结论 我们的研究表明特定 GABA 能和胆碱能神经元群体的产前发育与日后对精神分裂症的易感性有关，并提供了一张在 GE 细胞中运行的预测调控基因组元件图谱。