Association between mitochondria-related genes and cognitive performance in the PsyCourse Study

Kohshour, Mojtaba Oraki; Schulte, Eva C.; Heilbronner, Urs; Budde, Monika; Kálmán, Jánoš; Senner, Fanny; Heilbronner, Maria; Reich‐Erkelenz, Daniela; Schaupp, Sabrina K.; Vogl, Thomas; Adorjan, Kristina; Anghelescu, Ion‐George; Arolt, Volker; Baune, Bernhardt T.; Dannlowski, Udo; Dietrich, Detlef E.; Fallgatter, Andreas J.; Figge, Christian; Jäger, Markus; Lang, Fabian; Juckel, Georg; Konrad, Carsten; Reimer, Jens; Reininghaus, Eva; Schmauß, Max; Spitzer, Carsten; Hagen, Martin von; Wiltfang, Jens; Zimmermann, Jörg; Andlauer, Till F. M.; Nöthen, Markus M.; Degenhardt, Franziska; Forstner, Andreas J.; Rietschel, Marcella; Witt, Stephanie H.; Fischer, André; Falkai, P.; Papiol, Sergi; Schulze, Thomas G.

doi:10.1016/j.jad.2023.01.013

Cited by 2 publications

(2 citation statements)

References 25 publications

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“…4G). As mitochondrial dysfunction has been reported to be associated with GABA dysfunction 41 and etiology of SCZ 42,43 , our study provided evidence how mitochondrial dysfunction may contribute to SCZ risk.…”

Section: Discussionsupporting

confidence: 54%

Human forebrain organoids-based multi-omics analyses reveal PCCB's regulation on GABAergic system contributing to schizophrenia

Zhang

et al. 2023

Preprint

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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 (including FUSION, PrediXcan, summary-data-based Mendelian randomization (SMR), joint-tissue imputation approach with Mendelian randomization (MR-JTI)), 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 SNP rs35874192, an eQTL SNP for PCCB, showed differential allelic effects on transcriptional activities. PCCB knockdown in human forebrain organoids (hFOs) followed by RNA-seq revealed dysregulation of genes enriched with multiple neuronal functions including gamma-aminobutyric acid (GABA)-ergic synapse, as well as genes dysregulated in postmortem brains of SCZ patients or in cerebral organoids derived from SCZ patients. The metabolomic and mitochondrial function analyses confirmed the deceased GABA levels resulted from reduced 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 data and revealed that PCCB downregulation may contribute to SCZ risk through regulating GABAergic system, highlighting the mitochondrial function in SCZ.

show abstract

Section: Discussionsupporting

confidence: 54%

Human forebrain organoids-based multi-omics analyses reveal PCCB's regulation on GABAergic system contributing to schizophrenia

Zhang

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Our study highlighted that mitochondrial dysfunction caused by PCCB knockdown not only impaired cellular energy production, but also resulted into GABAergic dysfunction. Since mitochondrial dysfunction is associated with GABAergic dysfunction 42 and the etiology of SCZ 43 , 44 , our study connected the “mitochondrial hypothesis” and “GABA hypothesis” of SCZ.…”

Section: Discussionmentioning

confidence: 55%

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

Zhang,

et al. 2023

Nat Commun

View full text Add to dashboard Cite

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.

show abstract

Association between mitochondria-related genes and cognitive performance in the PsyCourse Study

Cited by 2 publications

References 25 publications

Human forebrain organoids-based multi-omics analyses reveal PCCB's regulation on GABAergic system contributing to schizophrenia

Human forebrain organoids-based multi-omics analyses reveal PCCB's regulation on GABAergic system contributing to schizophrenia

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

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