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Impact of schizophrenia GWAS loci converge onto distinct pathways in cortical interneurons vs glutamatergic neurons during development

Molecular Psychiatry volume 27, pages 4218–4233 (2022)Cite this article

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Abstract

Remarkable advances have been made in schizophrenia (SCZ) GWAS, but gleaning biological insight from these loci is challenging. Genetic influences on gene expression (e.g., eQTLs) are cell type-specific, but most studies that attempt to clarify GWAS loci’s influence on gene expression have employed tissues with mixed cell compositions that can obscure cell-specific effects. Furthermore, enriched SCZ heritability in the fetal brain underscores the need to study the impact of SCZ risk loci in specific developing neurons. MGE-derived cortical interneurons (cINs) are consistently affected in SCZ brains and show enriched SCZ heritability in human fetal brains. We identified SCZ GWAS risk genes that are dysregulated in iPSC-derived homogeneous populations of developing SCZ cINs. These SCZ GWAS loci differential expression (DE) genes converge on the PKC pathway. Their disruption results in PKC hyperactivity in developing cINs, leading to arborization deficits. We show that the fine-mapped GWAS locus in the ATP2A2 gene of the PKC pathway harbors enhancer marks by ATACseq and ChIPseq, and regulates ATP2A2 expression. We also generated developing glutamatergic neurons (GNs), another population with enriched SCZ heritability, and confirmed their functionality after transplantation into the mouse brain. Then, we identified SCZ GWAS risk genes that are dysregulated in developing SCZ GNs. GN-specific SCZ GWAS loci DE genes converge on the ion transporter pathway, distinct from those for cINs. Disruption of the pathway gene CACNA1D resulted in deficits of Ca2+ currents in developing GNs, suggesting compromised neuronal function by GWAS loci pathway deficits during development. This study allows us to identify cell type-specific and developmental stage-specific mechanisms of SCZ risk gene function, and may aid in identifying mechanism-based novel therapeutic targets.

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Fig. 1: SCZ GWAS loci DE genes converge onto PKC pathway in developing cINs.
Fig. 2: ATP2A2 and DGKI expression regulates PKC activity.
Fig. 3: SCZ risk loci regulate ATP2A2 expression.
Fig. 4: SCZ GWAS loci DE genes converge onto ion transporter pathway in developing glutamatergic neurons.
Fig. 5: CACNA1D dysregulation impairs Ca2+ currents in developing glutamatergic neurons.

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Acknowledgements

We thank Karen F. Berman, MD and Jose Apud, MD Ph.D. at the National Institute of Mental Health for their contribution in providing patient fibroblast samples. We thank Daniel R. Weinberger, M.D. at the Lieber Institute for Brain Development for supplying patient fibroblast samples and for critical review of the manuscript.

Funding

This study was supported by MH125246 (PR), MH116442 (PR), MH118339 (J-HC). DP2MH122403 (HW), MH107884 (SC), NS121541 (SC) and NYSTEM C32607GG (SC).

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Authors and Affiliations

  1. Department of Cell biology and Anatomy, New York Medical College, Valhalla, NY, 10595, USA

    Dongxin Liu, Amy Zinski, Akanksha Mishra, Haneul Noh, Gun-Hoo Park, Yiren Qin, Oshoname Olorife, James M. Park, Chiderah P. Abani, Joy S. Park, Janice Fung, Farah Sawaqed, Xiaolei Zhang, Patric K. Stanton & Sangmi Chung

  2. Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, China

    Dongxin Liu

  3. Department of Psychiatry, McLean Hospital/Harvard Medical School, Belmont, MA, 02478, USA

    Haneul Noh, Joseph T. Coyle & Sangmi Chung

  4. Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY, 10029, USA

    Eli Stahl, Jaroslav Bendl, John F. Fullard & Panos Roussos

  5. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY, 10029, USA

    Eli Stahl, Jaroslav Bendl, John F. Fullard & Panos Roussos

  6. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY, 10029, USA

    Eli Stahl, Jaroslav Bendl, John F. Fullard & Panos Roussos

  7. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY, 10029, USA

    Jaroslav Bendl, John F. Fullard & Panos Roussos

  8. Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY, 10029, USA

    Jaroslav Bendl, John F. Fullard & Panos Roussos

  9. Mental Illness Research Education and Clinical Center (VISN 2 South), James J. Peters VA Medical Center, Bronx, NY, 10468, USA

    Panos Roussos

  10. Department of Pathology, New York Medical College, Valhalla, NY, 10595, USA

    Changhong Yin & Weihua Huang

  11. Department of Public Health, New York Medical College, Valhalla, NY, USA

    Hae-Young Kim

  12. Department of Genetics, University of North Carolina, Chapel Hill, NC, 27599, USA

    Hyejung Won

  13. Department of Molecular, Cell and Systems Biology, University of California, Riverside, CA, 92521, USA

    Jun-Hyeong Cho

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  1. Dongxin Liu
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Contributions

DL, AZ, AM, HN, G-HP, YQ, JB, JFF, PR, XZ, PS, J-HC and SC designed the experiments. DL, AZ, AM, HN, G-HP, YQ and JMP differentiated cortical interneurons and analyzed them by qPCR and immunocytochemistry. DL, JSP and FS performed arborization analysis. DL, AZ and JF performed synapse analysis. DL, AZ, OO and CA did Western blot analysis. JTC reviewed data interpretation and manuscript contents. ES provided SCZ GWAS fine mapping data. JB, JFF, PR and HW did ATAC-seq analysis. J-HC did patch clamp analysis in brain slices. XZ and PS did patch clamp analysis in culture. CY and WH did RNA-seq and ChiP-seq analysis. H-YK performed statistical analysis. DL, JB, JFF, PR, XZ, PKS, HW, J-HC and SC wrote the manuscript. PR, J-HC, HW and SC supported this study financially.

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Correspondence to Dongxin Liu or Sangmi Chung.

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Liu, D., Zinski, A., Mishra, A. et al. Impact of schizophrenia GWAS loci converge onto distinct pathways in cortical interneurons vs glutamatergic neurons during development. Mol Psychiatry 27, 4218–4233 (2022). https://doi.org/10.1038/s41380-022-01654-z

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  • DOI: https://doi.org/10.1038/s41380-022-01654-z

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