Division of Psychological Medicine and Clinical Neurosciences, Centre for Neuropsychiatric Genetics & Genomics, Cardiff University, Cardiff, UK.
Neuroscience and Mental Health Innovation Institute, Cardiff University, Cardiff, UK.
Schizophr Bull. 2024 Aug 27;50(5):1171-1184. doi: 10.1093/schbul/sbae083.
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.
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.
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.
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.
神经节隆起（GE）是胎儿特异性结构，可产生前脑的γ-氨基丁酸（GABA）和乙酰胆碱释放神经元。鉴于精神分裂症中存在 GABA 能、胆碱能和神经发育障碍的证据，我们测试了 GE 神经元发育在介导该疾病遗传风险中的潜在作用。
我们结合了精神分裂症的一项最近的大规模全基因组关联研究的数据和来自人类 GE 的单细胞 RNA 测序数据，以测试在高表达特异性发育 GE 细胞群的基因中，精神分裂症风险变异的富集情况。我们还进行了单个核 Assay for Transposase-Accessible Chromatin with Sequencing（snATAC-Seq），以绘制在人类 GE 的单个细胞群体中可能起作用的潜在调节基因组区域，并用这些来测试精神分裂症常见遗传变异易感性的富集情况，并对与该疾病相关的非编码变异进行功能注释。
精神分裂症常见变异易感性在高表达特异性发育神经元群体的基因中富集，这些基因预测形成多巴胺 D1 和 D2 受体表达的 GABA 能纹状体中间神经元、皮质 somatostatin 阳性 GABA 能中间神经元、钙调蛋白阳性 GABA 能神经元和胆碱能神经元。与这些发现一致的是，精神分裂症的遗传风险集中在 GE 发育神经元群体中映射的预测调节基因组序列上。
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后来易患精神分裂症有关，并提供了在 GE 细胞中起作用的预测调节基因组元件图谱。
