Researchers Discover Genetic Markers Associated with Bone Growth

Genetic markers related to mineral bone accrual could help providers identify younger patients at risk of fractures in later life, according to a study published in Genome Biology.

Osteoporosis is a chronic disease characterized by low bone mineral density (BMD) and strength, which subsequently increases the risk of fracture.

While osteoporosis is generally considered a disease of old age, the accrual of bone density in early life is critical for achieving optimal bone mass in adulthood and influences bone health throughout a person’s life. Although studies have looked at genetic markers associated with bone health in adulthood, very few have been performed in children during the most critical period of bone growth.

Genome-wide association studies (GWAS) have also attempted to pinpoint genetic markers associated with bone growth, but an improved understanding of the spatial organization of the human genome can reveal underlying causal genes that may otherwise been missed.

"We wanted to do a GWAS study that measured bone mineral accrual at multiple time points to provide us with proper longitudinal data at ages when the skeleton is growing and developing," said Struan F.A. Grant, PhD, Director of the Center for Spatial and Functional Genomics and the Daniel B. Burke Endowed Chair for Diabetes Research at Children’s Hospital of Philadelphia (CHOP) and lead author of the study.

"By doing a longitudinal study, we had much greater power in a relatively small cohort of patients."

The research team compiled data from approximately 11,000 bone density measurements that were conducted as part of the Bone Mineral Density in Childhood Study (BMDCS). After identifying the genetic markers, researchers used a variant-to-gene mapping method to look for both underlying causal variants as well as corresponding effector genes.

The group further investigated specific genetic markers, or loci, to characterize their impact on osteoblast function.

With this method, researchers identified 40 distinct loci, including 35 that hadn’t been previously reported, associated with bone accrual. Several of these loci are associated with fracture risk later in life. The team also identified two novel effector genes that are potentially causative, as well as multiple genetic pathways involved in variation in bone accrual.

These genetic pathways have important roles in determining whether cells eventually become osteoblasts (bone cells) or adipocytes (fat cells).

The results of the study could lead to earlier, targeted interventions to preserve bone health throughout patients’ lives.

"This study is one of many that demonstrates how these loci are manifesting themselves earlier in life than we had previously thought," said Babette S. Zemel, PhD, Associate Program Director of the Clinical and Translational Research Center, Director of the Bionutrition Core Laboratory at CHOP and first author of the study.

"In this case, our findings may help us better tailor lifestyle interventions, such as exercise and dietary changes, that will help patients later in life, and they may also lead to novel therapeutic interventions."

Genomic data has played an increasingly significant role in understanding disease risk and improving care management. In a recent study, researchers analyzed genomic data from diverse populations to improve risk scores for prostate cancer and enable early detection of the disease.

The team identified 86 new genetic variations that increase risk for prostate cancer, not previously discovered, bringing the total number of risk loci for prostate cancer to 269.

“We not only found new markers of risk, but also demonstrated that, by combining genetic information across populations, we were able to identify a risk profile that can be applied across populations,” said corresponding author Christopher Haiman, ScD, professor of preventive medicine at the Keck School of Medicine of USC and director of the USC Center for Genetic Epidemiology.

“This emphasizes the value of adding multiple racial and ethnic populations into genetic studies.”