A combination of powerful tools has helped scientists identify two new genes that could contribute to osteoporosis through their effect on bone density. The finding could lead to better treatments for the bone-weakening disease.

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It may soon be possible to predict osteoporosis before it develops.

The study, by researchers at the Children’s Hospital of Philadelphia (CHOP) in Pennsylvania, highlights the importance of understanding the 3D geography of the genome in locating genes that cause disease.

The team points out that identifying DNA variants, or differences, behind diseases, is not necessarily enough to locate the genes that cause the disease. The variants, for example, could be triggers of genes in other parts of the genome.

In a paper that now features in the journal Nature Communications, the researchers describe how they probed the 3D geography of DNA in bone-forming cells to locate genes that might influence bone mineral density.

They suggest that their methods could also help to study other genetic conditions, including pediatric diseases.

“The geography of the genome is not linear,” says co-senior study author Struan F. A. Grant Ph.D., who is a director of the Center for Spatial and Functional Genomics at CHOP.

“Because DNA is folded into chromosomes,” he explains, “parts of the genome may come into physical contact, enabling key biological interactions that affect how a gene is expressed. That’s why we study the three-dimensional structure of the genome.”

Osteoporosis is a disease that progressively weakens the bones and increases the risk of fracture, especially in the wrist, spine, and hip.

Bone tissue is alive and perpetually adds new bone and removes old bone. In childhood, the process favors the formation of new tissue, allowing bones to grow and get stronger.

However, as people age, bone formation peaks and then lags further and further behind bone removal, with the result that bones get progressively less dense and weaker.

The National Institutes of Health (NIH) estimate that there are more than 53 million people in the United States who already have osteoporosis or are at high risk of developing it because of low bone mineral density.

Scientists unraveled the human genome more than 10 years ago. Since then, many genome-wide association studies (GWAS) have identified variants, or building block sequences in DNA, that are more common in people with particular diseases.

In their study paper, Dr. Grant and his colleagues state that osteoporosis has “an essential genetic component.”

However, they go on to explain that while GWAS have uncovered DNA variants that are “robustly associated with bone mineral density,” this is not the same as finding the genes that actually control the bone-forming process.

So, the purpose of their study was to use GWAS-derived locations of bone mineral density variants in a high-resolution, 3D “variant-to-gene mapping” exercise in human osteoblasts, which are cells that make new bone.

This exercise involved analyzing the 3D geography of the tightly-folded and packaged DNA within chromosomes. Using a special “spatial genomics” technique, the team was able to map the “genome-wide interactions” between GWAS-derived bone mineral density variants and the rest of the genome.

In doing this, they observed “consistent contacts” to potential causal genes from around 17 percent of the 273 GWAS-derived bone mineral density locations that they investigated.

This led to the identification of two new genes with a potential “causative role” in osteoporosis: ING3 and EPDR1. The team confirmed the genes’ strong role by demonstrating that silencing them stops osteoblasts from forming new bone.

The researchers note that there could be more “causative genes” in addition to these. However, they also point out that the variant that links to ING3 relates strongly to the density of bone in the wrist, which is the most common “site of fracture in children.”

They suggest that further studies into the biological pathways involving ING3 could lead to new treatments to strengthen bone and prevent fracture.

He and his team are already working with other groups at CHOP and at other institutions to create variant-to-gene “atlases” for other types of cell. These should prove valuable for the development of new treatments for many diseases, including “pediatric cancers, diabetes, and lupus,” says Dr. Grant.

We have identified two novel genes that affect bone-forming cells relevant to fractures and osteoporosis. Furthermore, the research methods we used could be applied more broadly to other diseases with a genetic component.”

Struan F. A. Grant Ph.D.