Genome-wide CRISPR screening of chondrocyte maturation newly implicates genes in skeletal growth and height-associated GWAS loci

John M Baronas; Eric Bartell; Anders Eliasen; John G Doench; Loic Yengo; Sailaja Vedantam; Eirini Marouli; GIANT Consortium; Henry M Kronenberg; Joel N Hirschhorn; Nora E Renthal

doi:10.1016/j.xgen.2023.100299

Genome-wide CRISPR screening of chondrocyte maturation newly implicates genes in skeletal growth and height-associated GWAS loci

Cell Genom. 2023 Apr 14;3(5):100299. doi: 10.1016/j.xgen.2023.100299. eCollection 2023 May 10.

Authors

John M Baronas¹, Eric Bartell^{1

2

3}, Anders Eliasen^{1

2

4

5}, John G Doench⁶, Loic Yengo⁷, Sailaja Vedantam^{1

2}, Eirini Marouli⁸; GIANT Consortium; Henry M Kronenberg⁹, Joel N Hirschhorn^{1

2}, Nora E Renthal¹

Affiliations

¹ Department of Pediatrics, Division of Endocrinology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
² Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³ Department of Genetics, Harvard Medical School, Boston, MA, USA.
⁴ COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
⁵ Department of Health Technology, Section for Bioinformatics, Technical University of Denmark, Kgs. Lyngby, Denmark.
⁶ Genetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁷ Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.
⁸ William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
⁹ Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

Abstract

Alterations in the growth and maturation of chondrocytes can lead to variation in human height, including monogenic disorders of skeletal growth. We aimed to identify genes and pathways relevant to human growth by pairing human height genome-wide association studies (GWASs) with genome-wide knockout (KO) screens of growth-plate chondrocyte proliferation and maturation in vitro. We identified 145 genes that alter chondrocyte proliferation and maturation at early and/or late time points in culture, with 90% of genes validating in secondary screening. These genes are enriched in monogenic growth disorder genes and in KEGG pathways critical for skeletal growth and endochondral ossification. Further, common variants near these genes capture height heritability independent of genes computationally prioritized from GWASs. Our study emphasizes the value of functional studies in biologically relevant tissues as orthogonal datasets to refine likely causal genes from GWASs and implicates new genetic regulators of chondrocyte proliferation and maturation.

Keywords: chondrocyte; epiphysis; genome-wide CRISPR screen; genome-wide association studies; growth plate; height; skeletal growth.

Abstract

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