Researchers ID Hundreds of Genetic Factors of Osteoporosis

January 2, 2019
Researchers ID Hundreds of Genetic Factors of Osteoporosis
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An international research team has generated an “atlas” of hundreds of genetic factors linked with estimated bone mineral density (eBMD), which is one of the most important clinically relevant risk factors when diagnosing osteoporosis. Carried out by a team at the Lady Davis Institute (LDI) at the Jewish General Hospital (JGH), the genome-wide association study (GWAS) in more than 420,000 individuals enrolled in the U.K. Biobank, identified more than 500 genetic loci—including 301 new genetic factors—which together explained 20% of the genetic variance associated with osteoporosis. Subsequent studies in knockout mice that were engineered to lack target genes confirmed the relevance of many of the identified loci to skeletal phenotype.

The researchers hope that their findings will give scientists new insights into the development of osteoporosis, and will also point to new therapeutic approaches. “Our findings represent significant progress in highlighting drug development opportunities,” suggested research lead Brent Richards, MD, a geneticist at the LDI’s Centre for Clinical Epidemiology who treats osteoporosis patients at his practice at the JGH and is also a professor of medicine, human genetics, and epidemiology and biostatistics at McGill University. “This set of genetic changes that influence BMD provides drug targets that are likely to be helpful for osteoporotic fracture prevention.”

Richards and colleagues reported their findings in a paper in Nature Genetics, which is titled, “An atlas of genetic influences on osteoporosis in humans and mice.”

Osteoporosis is a common age-related disorder characterized by decreased bone strength and increased risk of bone fracture, the authors wrote. BMD is the most clinically relevant risk factor when diagnosing osteoporosis, and is a key risk factor for fracture. “BMD genome-wide association studies (GWASs) have demonstrated that it is a highly polygenic trait, and the known genetic determinants of fracture all act through BMD,” they stated.

“We currently have few treatment options,” said Richards. “… many patients who are at high risk of fractures do not take current medications because of fear of side effects. Notwithstanding that it is always better to prevent than to treat. We can prescribe injectables that build bone, but they are prohibitively expensive. We have medications that prevent loss of bone, but they must be taken on a strict schedule. As a result, the number of people who should be treated, but are not, is high. Therefore, we believe that we will have greater success in getting patients to follow a treatment regimen when it can be simplified.”

The researchers had previously identified 203 loci linked with eBMD, by evaluating quantitative heel ultrasound measurements, which they say explain 12% of the variance. “eBMD is predictive of fracture and is highly heritable (50–80%),” they wrote. “While BMD measured from dual-energy x-ray absorptiometry (DXA) scanning is most often used in clinical settings, our recent eBMD GWAS identified 84% of all currently known genome-wide significant loci for DXA-derived BMD.”

For the new investigation, the team undertook an eBMD GWAS of 426,824 individuals enrolled in the U.K. Biobank. They claim that the study is the largest ever undertaken to discover genetic determinants of osteoporosis. The analyses identified 518 genome-wide significant loci, 301 of which were novel. A further meta-analysis of 1.2 million individuals identified 13 fracture loci, all of which were also associated with BMD and/or eBMD.

The relevance of 126 target genes to skeletal phenotype was then verified in knockout mice, each engineered to lack one of the identified eBMD-relevant genes. Detailed studies indicated that one of these genes, DAAM2, represents a key eBMD target gene linked with bone strength and fracture. “Disruption of DAAM2 in mice led to increased cortical porosity and marked bone composition and strength reduction and decreased mineralization in human osteoblasts,” the authors commented. They also identified CBX1, WAC, DSCC1, RGCC, and YWHAE as additional eBMD target genes, for which there was evidence of an association with fracture. “These five genes had contrasting abnormalities of bone structure and strength when deleted in mice, emphasizing their functional role in skeletal physiology and importance for further study,” the authors stated.

They hope that the findings will help scientists understand the pathophysiology of osteoporosis, as well as open up new drug development opportunities. “Although we found many genetic factors associated with BMD, the kind of precision medicine that genetics offers should allow us to hone in on those factors that can have the greatest effect on improving bone density and lessening the risk of fracture,” commented John Morris, also from the LDI and McGill University, and who is the lead author of the published study.

“The polygenicity of eBMD is striking,” the authors wrote. “Few traits and diseases currently have hundreds of loci associated at genome-wide significance. This has led to a large proportion of total eBMD variance being explained by now-known genetic determinants, which will facilitate bone biology studies and enable osteoporosis drug development … In-depth analysis of one gene, DAAM2, showed a disproportionate decrease in bone strength relative to mineralization. This genetic atlas provides evidence linking associated SNPs to causal genes, offers new insight into osteoporosis pathophysiology, and highlights opportunities for drug development.”

The researchers acknowledge that their study has some important limitations, including the use of eBMD instead of DXA-derived BMD, which is a measurement typically carried out in the clinic. “Nonetheless, beyond their phenotypic correlation, these two traits have high genetic concordances in terms of their genome-wide significant loci, suggesting that underlying biological properties of these two traits are similar,” they wrote. “Importantly, eBMD is a strong predictor of fracture risk in its own right and contributes to risk assessment over and above DXA-derived BMD at the hip.”

“In summary, we have generated an atlas of genetic influences on osteoporosis in humans and mice,” they concluded. “We have more fully described the genetic architecture of eBMD and fracture and identified target genes strongly enriched for known roles in bone biology. … We expect these target genes to include new drug targets for the treatment of osteoporosis, a common disease for which new therapeutic options are a priority.”