NEW YORK — Researchers at Boston Children's Hospital have mapped 145 genes and related pathways involved in the maturation and proliferation of chondrocytes, particularly growth-plate chondrocytes that are involved in bone growth. These genes play a critical role in human height.
"Our study was motivated by the desire to better understand the genetic basis of bone growth and variation in height," corresponding author Nora Renthal, medical director of the bone health program at Boston Children's Hospital, said in an email.
While previous genome-wide association studies (GWASs) have aided in the understanding of the genetics of skeletal growth, not many studies have been able to translate genetic associations to biological mechanisms, the authors noted.
"Most GWAS variants reside in noncoding regions, with no universally accepted approach to assign SNPs to relevant genes, [meaning] that it is difficult to identify the causal genes mediating associations seen in GWASs," the authors wrote.
For this study, published in Cell Genomics on Friday, Renthal and colleagues developed and implemented a CRISPR-based method to conduct functional genome-wide knockout (KO) screens in growth-plate-like chondrocytes (GPLC).
At two time points — days 4 and 15 post-knockout — the researchers assayed more than 600 million KO GPLCs to check if they were maturing faster or slower than expected.
They found around 140 genes that, when knocked out, affected GPLC maturation. Among them, 10 percent of the genes altering GPLC maturation were members of a curated list of 581 Online Mendelian Inheritance in Man genes known to cause monogenic skeletal growth disorders.
These genes also included ones implicated in GPLC maturation. At least 13 genes identified are involved in pathways linked to skeletal growth, including two negative regulators of the Indian hedgehog (IHH) signaling pathway.
"I hope that this work will help patients with skeletal dysplasia and other skeletal disorders by providing new drug targets for future investigation," Renthal said. "For example, drugs that target specific genes or pathways involved in chondrocyte proliferation and maturation could be developed to help promote bone growth in individuals with skeletal dysplasias."
The researchers additionally examined whether genes prioritized by height GWASs between 2010 and 2022 were enriched among the genes identified, finding that those GWAS-prioritized genes significantly affected chondrocyte maturation when knocked out. "Our study suggests that genome-wide functional assays in chondrocytes could be a valuable tool for refining SNP-to-gene assignment in future height GWASs," the authors wrote.
While this study identified several novel genetic targets that appear to be associated with both functional changes in chondrocytes and height GWAS, it did not narrow down the entire set of markers and genes that contribute to height, Renthal noted. "However, our findings do represent an important step forward in our understanding of this complex trait, and we hope they will help guide future research in this area," she said.