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Osteoporosis: Finding the genes for fragile bones

eLife

23 Dec 2022

Kague E.

Bone fractures are painful and debilitating, particularly as we get older. However, some people are more susceptible than others to breaking bones as they age. Osteoporosis is the most prevalent bone condition of the ageing population (Salari et al., 2021). It is characterized by low bone mass and the deterioration of bone microarchitecture, leading to porous bones that are more likely to break (Trajanoska et al., 2018). But what are the causes of osteoporosis?

Studies involving twins and families have taught us that osteoporosis is heritable (Ralston and Uitterlinden, 2010), which means that genetics play a vital role in determining whether someone is at risk of developing osteoporosis. Learning which genes cause osteoporosis could teach us how the condition develops, opening therapeutic avenues to treat it.

This rationale has inspired researchers to perform genome-wide association studies (GWAS) to identify regions of the genome associated with bone mineral density, which is the trait that is the best indicator of fracture risk (Timpson et al., 2018). It has been 15 years since the first bone mineral density GWAS (Kague et al., 2022). The largest of these studies, published in 2019, involved around 425,000 participants and successfully identified over 500 genomic regions associated with bone mineral density of the heel (Morris et al., 2019).

However, interpreting the associations captured with GWAS can be challenging, because the loci that are identified can contain several genes, reside in non-coding regions near genes, or contain no genes at all. Therefore, despite the remarkable progress made by bone mineral density GWAS, the field needs to bridge a considerable gap that lies between correlation and causation. Filling this gap is essential to understand the underlying biology of osteoporosis and find potential therapeutics for the condition.

Now, in eLife, Charles R Farber and colleagues from the University of Virginia, the University of Colorado and Boston University – including Basel Maher AI-Barghouthi as first author – report on a systematic way to narrow down GWAS signals and shed light on the genes that are likely responsible for variations in human bone mineral density (Al-Barghouthi et al., 2022). To do this, the group leveraged transcriptomic data and computational approaches to systematically screen published bone mineral density GWAS (Figure 1). They identified 512 genes that could be regulators of bone mineral density, including the gene PPP6R3, which had not been associated with bone before.

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