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

Highlights

• Genome-wide CRISPR KO study links growth-plate maturation to height GWASs

• Identified 145 genes affecting chondrocyte proliferation and maturation

• Screening targets independently predict enrichment of GWAS height heritability

• Method could be used to improve existing GWAS gene assignment algorithms

Summary

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.