Coexpression enrichment analysis at the single-cell level reveals convergent defects in neural progenitor cells and their cell-type transitions in neurodevelopmental disorders
- Kaifang Pang1,2,3,11,
- Li Wang2,4,5,6,11,
- Wei Wang2,4,
- Jian Zhou2,4,
- Chao Cheng7,8,
- Kihoon Han9,
- Huda Y. Zoghbi1,2,4,10 and
- Zhandong Liu1,2,3
- 1Department of Pediatrics-Neurology, Baylor College of Medicine, Houston, Texas 77030, USA;
- 2Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas 77030, USA;
- 3Computational and Integrative Biomedical Research Center, Baylor College of Medicine, Houston, Texas 77030, USA;
- 4Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA;
- 5Department of Neurology, University of California, San Francisco, San Francisco, California 94143, USA;
- 6The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, California 94143, USA;
- 7Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA;
- 8Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, Texas 77030, USA;
- 9Department of Neuroscience, College of Medicine, Korea University, Seoul 02841, South Korea;
- 10Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas 77030, USA
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↵11 These authors contributed equally to this work.
Abstract
A large number of genes have been implicated in neurodevelopmental disorders (NDDs), but their contributions to NDD pathology are difficult to decipher without understanding their diverse roles in different brain cell types. Here, we integrated NDD genetics with single-cell RNA sequencing data to assess coexpression enrichment patterns of various NDD gene sets. We identified midfetal cortical neural progenitor cell development—more specifically, the ventricular radial glia-to-intermediate progenitor cell transition at gestational week 10—as a key point of convergence in autism spectrum disorder (ASD) and epilepsy. Integrated Gene Ontology–based analysis further revealed that ASD genes activate neural differentiation and inhibit cell cycle during the transition, whereas epilepsy genes function as downstream effectors in the same processes, offering one possible explanation for the high comorbidity rate of the two disorders. This approach provides a framework for investigating the cell-type-specific pathophysiology of NDDs.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.254987.119.
- Received July 19, 2019.
- Accepted June 11, 2020.
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