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Abstract：
Identifying genes whose expression is associated with schizophrenia (SCZ) risk by transcriptome-wide association studies (TWAS) facilitates downstream experimental studies. Here, we integrated multiple published datasets of TWAS, gene coexpression, and differential gene expression analysis to prioritize SCZ candidate genes for functional study. Convergent evidence prioritized Propionyl-CoA Carboxylase Subunit Beta (PCCB), a nuclear-encoded mitochondrial gene, as an SCZ risk gene. However, the PCCB\'s contribution to SCZ risk has not been investigated before. Using dual luciferase reporter assay, we identified that SCZ-associated SNPs rs6791142 and rs35874192, two eQTL SNPs for PCCB, showed differential allelic effects on transcriptional activities. PCCB knockdown in human forebrain organoids (hFOs) followed by RNA sequencing analysis revealed dysregulation of genes enriched with multiple neuronal functions including gamma-aminobutyric acid (GABA)-ergic synapse. The metabolomic and mitochondrial function analyses confirmed the decreased GABA levels resulted from inhibited tricarboxylic acid cycle in PCCB knockdown hFOs. Multielectrode array recording analysis showed that PCCB knockdown in hFOs resulted into SCZ-related phenotypes including hyper-neuroactivities and decreased synchronization of neural network. In summary, this study utilized hFOs-based multi-omics analyses and revealed that PCCB downregulation may contribute to SCZ risk through regulating GABAergic pathways, highlighting the mitochondrial function in SCZ.
摘要：
通过全转录组关联研究（TWAS）鉴定其表达与精神分裂症（SCZ）风险相关的基因有助于下游实验研究。这里,我们整合了多个已发布的TWAS数据集，基因共表达，和差异基因表达分析，以优先考虑SCZ候选基因进行功能研究。融合证据优先考虑丙酰辅酶A羧化酶亚基β(PCCB)，核编码的线粒体基因,作为SCZ风险基因。然而,以前没有调查过PCCB对SCZ风险的贡献。使用双荧光素酶报告基因测定，我们确定了与SCZ相关的SNPrs6791142和rs35874192，PCCB的两个eQTLSNP，对转录活性显示出不同的等位基因效应。人前脑类器官（hFOs）中的PCCB敲低，然后进行RNA测序分析，揭示了富含多种神经元功能的基因的失调，包括γ-氨基丁酸（GABA）-能突触。代谢组学和线粒体功能分析证实了PCCB敲低hFO中抑制三羧酸循环导致的GABA水平降低。多电极阵列记录分析表明，hFO中的PCCB敲低导致SCZ相关表型，包括神经活动过度和神经网络同步性降低。总之,这项研究利用基于hFOs的多组学分析，并揭示PCCB下调可能通过调节GABA能途径导致SCZ风险，强调SCZ中的线粒体功能。
