Genetic implication of prenatal GABAergic and cholinergic neuron development in susceptibility to schizophrenia.
Genetic implication of prenatal GABAergic and cholinergic neuron development in susceptibility to schizophrenia.
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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。
DOI：
10.1101/2023.12.14.23299948
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Bray,NicholasJ
中科院分区：
文献类型：
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作者：
Cameron,Darren;Vinh,Ngoc-Nga;Prapaiwongs,Parinda;Perry,ElizabethA;Walters,JamesTR;Li,Meng;O'Donovan,MichaelC;Bray,NicholasJ
背景神经节突（GE）是胎儿特有的结构，可以产生前脑的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参与。研究设计：我们将最近一项大规模精神分裂症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，以测试在发育的GE细胞群体中具有高表达特异性的基因中精神分裂症风险变异的富集程度。此外，我们还进行了转座酶可及染色质测序单核测定（snATAC-Seq），以绘制人类GE单个细胞群中潜在的调控基因组区域，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程度，并对与该疾病相关的非编码变异进行功能注释。研究结果精神分裂症常见变异倾向基因在发育神经元群体中具有高表达特异性，这些神经元群体预计将形成表达多巴胺D1和D2受体的纹状体中棘神经元、皮质生长抑素阳性的gabaergy中间神经元、calretinin阳性的gabaergy神经元和胆碱能神经元。与这些发现一致，精神分裂症的遗传风险集中在GE发育神经元群体中预测的调节基因组序列中。结论sour研究提示gaba能和胆碱能神经元特定群体的产前发育与后期精神分裂症易感性有关，并提供了GE细胞中可预测的调控基因组元件图谱。
BackgroundThe 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 DesignWe 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 ResultsSchizophrenia 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.ConclusionsOur 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.