Impact of Schizophrenia GWAS Loci Converge Onto Distinct Pathways in Cortical Interneurons vs Glutamatergic Neurons During Development

Authors

Dongxin Liu, Department of Cell biology and Anatomy, New York Medical College, Valhalla, NY, 10595, USA. dxliu@cmu.edu.cn.
Amy Zinski, Department of Cell biology and Anatomy, New York Medical College, Valhalla, NY, 10595, USA.
Akanksha Mishra, Department of Cell biology and Anatomy, New York Medical College, Valhalla, NY, 10595, USA.
Haneul Noh, Department of Cell biology and Anatomy, New York Medical College, Valhalla, NY, 10595, USA.
Gun-Hoo Park, Department of Cell biology and Anatomy, New York Medical College, Valhalla, NY, 10595, USA.
Yiren Qin, Department of Cell biology and Anatomy, New York Medical College, Valhalla, NY, 10595, USA.
Oshoname Olorife, Department of Cell biology and Anatomy, New York Medical College, Valhalla, NY, 10595, USA.
James M. Park, Department of Cell biology and Anatomy, New York Medical College, Valhalla, NY, 10595, USA.
Chiderah P. Abani, Department of Cell biology and Anatomy, New York Medical College, Valhalla, NY, 10595, USA.Follow
Joy S. Park, Department of Cell biology and Anatomy, New York Medical College, Valhalla, NY, 10595, USA.
Janice Fung, Department of Cell biology and Anatomy, New York Medical College, Valhalla, NY, 10595, USA.
Farah Sawaqed, Department of Cell biology and Anatomy, New York Medical College, Valhalla, NY, 10595, USA.
Joseph T. Coyle, Department of Psychiatry, McLean Hospital/Harvard Medical School, Belmont, MA, 02478, USA.
Eli Stahl, Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY, 10029, USA.
Jaroslav Bendl, Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY, 10029, USA.
John F. Fullard, Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY, 10029, USA.
Panos Roussos, Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY, 10029, USA.
Xiaolei Zhang, Department of Cell biology and Anatomy, New York Medical College, Valhalla, NY, 10595, USA.
Patric K. Stanton, Department of Cell biology and Anatomy, New York Medical College, Valhalla, NY, 10595, USA.
Changhong Yin, Department of Pathology, New York Medical College, Valhalla, NY, 10595, USA.
Weihua Huang, Department of Pathology, New York Medical College, Valhalla, NY, 10595, USA.
Hae-Young Kim, Department of Public Health, New York Medical College, Valhalla, NY, USA.
Hyejung Won, Department of Genetics, University of North Carolina, Chapel Hill, NC, 27599, USA.
Jun-Hyeong Cho, Department of Molecular, Cell and Systems Biology, University of California, Riverside, CA, 92521, USA.
Sangmi Chung, Department of Cell biology and Anatomy, New York Medical College, Valhalla, NY, 10595, USA. schung8@nymc.edu.

Author Type(s)

Faculty

Journal Title

Molecular Psychiatry

First Page

4218

Last Page

4233

Document Type

Article

Publication Date

10-1-2022

Department

Cell Biology and Anatomy

Second Department

Pathology, Microbiology and Immunology

Third Department

Pharmacology

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 Ca 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.

Recommended Citation

Liu, D., Zinski, A., Mishra, A., Noh, H., Park, G., Qin, Y., Olorife, O., Park, J. M., Abani, C. P., Park, J. S., Fung, J., Sawaqed, F., Coyle, J. T., Stahl, E., Bendl, J., Fullard, J. F., Roussos, P., Zhang, X., Stanton, P. K., Yin, C., Huang, W., Kim, H., Won, H., Cho, J., & Chung, S. (2022). Impact of Schizophrenia GWAS Loci Converge Onto Distinct Pathways in Cortical Interneurons vs Glutamatergic Neurons During Development. Molecular Psychiatry, 27 (10), 4218-4233. https://doi.org/10.1038/s41380-022-01654-z