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Meta-analysis identified 56 genetic variants linked to osteoporosis, 14 to fracture risk
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Fifty-six loci associated with bone mineral density and 14 bone mineral density-associated loci related to fracture risk have been identified in a large meta-analysis of genome-wide association studies of osteoporosis.
Previous genome-wide association studies (GWAS) have identified 24 loci that influence BMD variation, researchers at the Institute for Aging Research at Hebrew SeniorLife, an affiliate of Harvard Medical School, wrote in a paper published in Nature Genetics.
According to the researchers, new genes identified in the study may provide insight into anabolic osteoporosis drug discovery. As of now, traditional treatments focus on decreasing bone resorption (bisphosphonates and RANKL inhibitors).
“In this report of the largest GWAS for osteoporosis traits to date, we identified 32 new genomic loci, bringing the total number of loci robustly associated with BMD variation to 56. Furthermore, we report that six of these BMD-associated loci are also associated with low-trauma fractures at P<53×10–8, an association that has not previously been detected,” the researchers wrote.
Three main stages were performed to garner results: 1) the discovery of BMD loci, 2) follow-up replication and 3) association of the BMD-associated loci with fracture.
Karol Estrada, MSc, a researcher in the department of internal medicine at Erasmus Medical Center in Rotterdam, the Netherlands, and colleagues examined data from 17 studies and 32,961 patients of European and East Asian ancestry. Researchers then replicated findings by examining data from 34 additional studies that involved 50,933 additional participants, all of whom received bone density scans and genotyping.
The data from the 34 additional studies were compared with findings from 31,016 participants with a history of fracture and 102,444 control participants.
The researchers said loci that were not previously known to have a role in bone biology were discovered through the study.
Based on the overall analysis, single nucleotide polymorphisms in 34 loci outperformed genome-wide significance, and 82 loci were associated at P<53×10–6, the researchers wrote.
Future studies on fracture risk must address the unidentified, independent risk for fracture, they wrote.
Disclosure: The researchers affiliated with deCODE genetics in Reykjavik, Iceland, hold stock options in that company. The other researchers report no relevant financial disclosures.
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Clifford J. Rosen, MD
This is the largest genome-wide association study for bone density and for fractures. The number of subjects initially screened, then replicated and subsequently analyzed for fractures, provides confidence that most of the loci identified are not only significant but also have pathophysiologic implications through a variety of networks. Some of the genes have been previously identified, but new ones without a known role in bone biology were also uncovered.
The authors correctly surmised that hundreds of variants with small effects contribute to the genetic architecture of both bone density and fracture risk. Moreover, they show the importance of gender and site for bone density variation.
These findings emphasize the complexity of the heritable influences on osteoporosis risk and reinforce the difficulties of doing genetic screening for most cases of osteoporosis. On the other hand, these data provide important pathophysiologic insights, as well as new signals from the GWAS, suggesting there may be other pharmacologic targets that could be explored in further studies.
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