Coexpression enrichment analysis at the single-cell level reveals convergent defects in neural progenitor cells and their cell-type transitions in neurodevelopmental disorders

Kaifang Pang, Li Wang, Wei Wang, Jian Zhou, Chao Cheng, Kihoon Han, Huda Y. Zoghb, Zhandong Liu

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)835-848
Number of pages14
JournalGenome Research
Volume30
Issue number6
DOIs
Publication statusPublished - 2020 Jun

Bibliographical note

Funding Information:
This work was supported by the National Institute of General Medical Sciences (R01-GM120033), National Science Foundation-Division of Mathematical Sciences (DMS-1263932), Cancer Prevention and Research Institute of Texas (RP170387), Houston Endowment, the Hamill Foundation, and Chao Family Foundation (Z.L.), Huffington Foundation, Howard Hughes Medical Institute (H.Y.Z.). L.W. was supported by a predoctoral fellowship from Autism Speaks (#9120).

Funding Information:
We thank Shu Zhang and Fuchou Tang for kindly sharing the detailed clustering result of cell subtypes, which can be downloaded now from the NCBI Gene Expression Omnibus (GEO; https://www .ncbi.nlm.nih.gov/geo/), accession number GSE104276. We thank Mingshan Xue, Dmitry Velmeshev, Hyun-Hwan Jeong, and Ying-Wooi Wan for valuable discussions. We thank V.L. Brandt for editing the manuscript. This work was supported by the National Institute of General Medical Sciences (R01-GM120033), National Science Foundation–Division of Mathematical Sciences (DMS-1263932), Cancer Prevention and Research Institute of Texas (RP170387), Houston Endowment, the Hamill Foundation, and Chao Family Foundation (Z.L.), Huf-fington Foundation, Howard Hughes Medical Institute (H.Y.Z.). L.W. was supported by a predoctoral fellowship from Autism Speaks (#9120).

Publisher Copyright:
© 2020 Cold Spring Harbor Laboratory Press. All rights reserved.

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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