Researchers have identified new genes that govern skeletal growth, which highlight the key role that cartilage cells play in determining height.
The findings, published in Cell Genomics, show how functional tissue studies can home in on causal genes among the broad genetic regions flagged up by large-scale genomic studies.
The study is really about understanding the genetics of the skeleton, said senior investigator Nora Renthal, PhD, medical director at Boston Children’s Hospital bone health program.
“I hope that this work will help patients with skeletal dysplasia and other skeletal disorders by providing new drug targets for future investigation,” she told Inside Precision Medicine.
“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.”
Genome-wide association studies (GWASs) of height have collectively identified thousands of height-associated loci in over five million individuals. However, it has been difficult to pinpoint the causal genes mediating the associations that have been found.
To investigate further, the investigators screened 600 million mouse cartilage cells called growth-plate chondrocytes in vitro to identify genes that, when deleted, would alter their growth and maturation.
Cellular changes of this type at the growth plates capping long bones lead to their elongation and are known to affect people’s height.
The CRISPR-based, genome-wide functional knockout study revealed both known and novel genes and pathways in chondrocyte proliferation and maturation at early or late time points in culture, with 90% of genes validated in secondary screening.
Most were linked with skeletal disorders and are crucial for growth plate maturation and bone formation.
The 145 identified genes were then combined with data from GWASs of human height to find areas that overlapped and narrow down the regions of DNA responsible for determining stature.
The researchers found that many height genes flagged in GWASs led to the early maturation of cartilage cells, indicating their importance.
Genes significantly affecting chondrocyte maturation in vitro overlapped with GWAS height genes and independently predicted height heritability in a way not captured by current GWAS gene assignment algorithms.
“We provide evidence that GWAS and mechanistic studies provide complementary information, pointing toward genes of importance to human health, and that the combination can prioritize genes more effectively than either approach in isolation,” the researchers reported.
They added: “We hope that our current data will thus advance the field by providing a tool to advance future studies of individual genes and gene networks.” The tool is available at chondrocyte.shinyapps.io/Live.