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Human forebrain organoid-based multi-omics analyses of PCCB as a schizophrenia associated gene linked to GABAergic pathways

Author

Listed:
  • Wendiao Zhang

    (Central South University
    University of South China
    University of South China
    University of South China)

  • Ming Zhang

    (Central South University)

  • Zhenhong Xu

    (University of South China
    University of South China
    University of South China)

  • Hongye Yan

    (University of South China
    University of South China
    University of South China)

  • Huimin Wang

    (University of South China
    University of South China
    University of South China)

  • Jiamei Jiang

    (University of South China
    University of South China
    University of South China)

  • Juan Wan

    (University of South China
    University of South China
    University of South China)

  • Beisha Tang

    (University of South China
    University of South China
    University of South China
    Central South University)

  • Chunyu Liu

    (Central South University
    SUNY Upstate Medical University)

  • Chao Chen

    (Central South University
    Central South University
    Central South University
    Central South University)

  • Qingtuan Meng

    (University of South China
    University of South China
    University of South China
    University of South China)

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.

Suggested Citation

  • Wendiao Zhang & Ming Zhang & Zhenhong Xu & Hongye Yan & Huimin Wang & Jiamei Jiang & Juan Wan & Beisha Tang & Chunyu Liu & Chao Chen & Qingtuan Meng, 2023. "Human forebrain organoid-based multi-omics analyses of PCCB as a schizophrenia associated gene linked to GABAergic pathways," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40861-2
    DOI: 10.1038/s41467-023-40861-2
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    References listed on IDEAS

    as
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