Have you ever wondered why some people are taller than others? Our height, a defining characteristic of our physical appearance, is a product of the interplay between our genes and our environment.

By one estimate, about 80% of an individual’s height can be explained by the DNA sequence variations they have inherited, but exactly which genes are responsible for this effect and what they do to affect height are only partially understood.

According to a new study published in the journal Cell Genomics, clues to demystifying height genetics may lie in growth plates –- cartilage near the ends of bones that hardens as we develop as children. Once these growth plates close, they are replaced by hard bone and your height is locked-in for life.

Skeleton genetics

The new research has now identified a pool of genes that control the growth of these cartilaginous cells, and thus determine the length and shape of our bones, as well as our overall stature.

The study’s senior author, Nora Renthal from Boston Children’s Hospital and Harvard University, explains that understanding the genetics of the skeleton is crucial to understanding how bones grow. As a pediatric endocrinologist, she cares for children with skeletal diseases and hopes to uncover more about the relationship between genes, growth plates, and skeletal growth.

“We have uncovered several genes that are associated with functional changes in chondrocyte maturation (cells found in healthy cartilage) and many of which are also implicated by human height genome-wide association studies (GWAS),” Renthal told ZME Science.

To identify height-associated genes, the research team analyzed 600 million mouse cartilage cells called chondrocytes. They were looking for genes that, when deleted using CRISPR gene editing technology, could alter cell growth and maturation, ultimately affecting human height. This was a massive undertaking that involved a lot of painstaking effort and time.

“I felt like I was back in medical residency, pulling long hours in the hospital! However, it was also very rewarding to see the results of our hard work and to discover new insights into the genetic mechanisms that control bone growth,” Renthal said.

Overall, the search revealed 145 genes that, when knocked out, were linked to skeletal disorders. As such, these genes may be critical for healthy growth plate maturation and bone formation.

The researchers then compared these genes with data from genome-wide association studies (GWAS) of human height. These studies compare the DNA of thousands of participants of varying heights in order to identify hotspots where “height genes” are located. However, these hotspots often contain multiple genes that may have totally unrelated functions, making it challenging for researchers to study individual targets.

The comparison revealed that the genes affecting cartilage cells overlapped with hotspots from human height GWAS. This means that these cartilage cell genes very likely play a role in determining our stature. The team also found that many of the GWAS suggested height genes lead to early maturation in cartilage cells, suggesting that genetic changes affecting cartilage cell maturation may have a more significant impact on height.

“While our study did identify several novel genetic targets that appear to be associated with both functional changes in chondrocytes and height GWAS, we have not yet narrowed down the entire set of markers and genes that contribute to height. 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,” Renthal said.

Helping children fight bone growth disorders

The researchers note that while studies in mouse cells may not fully translate to humans, and GWAS are observational studies that cannot fully illustrate the cause and effect of height, the new study provides a novel method to bridge the two methods and provide new insights into human genetics.

The team plans to use this method to understand the effect of hormones on cartilage cells and investigate some of the 145 genes that have no known connection to skeletal growth. This investigation may reveal new genes and pathways that play a role in bone development.

Ultimately, understanding the biology of the growth plate can help researchers intervene earlier in the growing skeletons and the lives of children with skeletal dysplasia. By understanding more about how genetics affect bone growth, Renthal hopes that we can develop treatments that can improve their quality of life.

“I hope that our findings could potentially lead to new therapies for certain skeletal diseases by helping to identify the specific genes and pathways that are involved in bone growth,” she said, adding that:

“One interesting aspect of our research is that it highlights the power of collaboration and interdisciplinary approaches. Our study involved researchers from computational biology and cell/molecular biology, all working together to achieve a common goal. By combining our expertise and knowledge, we hope to have been able to make significant contributions to our understanding of bone growth and height variation.”