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Chromosome Locus and Candidate Gene for Osteoporosis Identified

  • Published: December 22, 2003
  • DOI: 10.1371/journal.pbio.0000085

While osteoporosis is commonly thought of as a disease of old women, it's really more a disease of old age. Marked by a deterioration of bone density and strength, osteoporosis (meaning “porous bones”) often goes undetected until a fateful slip results in a serious fracture of the hip, spine, or wrist. While it's true that postmenopausal women are much more susceptible than men—largely owing to their smaller frames—risk for men increases exponentially with age. Risk factors traditionally reflect lifestyle choices, including lack of exercise and poor diet, though genetics appears to be a major determinant of low bone mineral density (BMD), a characteristic feature of osteoporosis. Genetic factors also influence an individual's rate of bone loss, bone size, and likelihood of falling. In a large genetic study of osteoporotic Icelanders and their extended families, Unnur Styrkársdóttir and colleagues at deCODE Genetics in Reykjavik identified a candidate gene associated with a predisposition for osteoporosis.

Linking specific genes with complex diseases like osteoporosis is a tricky business. There are likely to be several genetic causes, and to find them researchers need large populations, abundant genetic markers, and extensive patient data. In addition to powerful genetic resources, researchers at deCODE can take advantage of a nationwide genealogical database of native Icelanders stretching back to the country's origins 1,100 years ago. By screening hundreds of affected individuals and their families, the scientists searched for candidate genes underlying osteoporosis and its harbinger, low BMD.

While low BMD is the best predictor of osteoporotic fracture, peak bone mass (mineral mass begins to diminish after young adulthood) and the rate of postmenopausal bone loss also appear to influence risk. Genetics contributes to all of these factors. Styrkársdóttir and colleagues screened the genealogical data on 207 extended families for the most clinically relevant phenotypic factors—low BMD and osteoporotic fractures—to focus their search. Screening only affected families with these attributes in a genome-wide scan, they say, seemed a reasonable method for finding susceptibility genes. They conducted a series of scans and found a significant linkage to the short arm of Chromosome 20. This region contains six known genes, including four genes involved in bone formation and osteoblast (bone-forming cell) differentiation.

To winnow the list of most likely candidate genes, Styrkársdóttir et al. screened the genomes of 705 individuals with osteoporosis in a case-control study, using closely spaced genetic markers within the region of interest. This analysis pointed to BMP2 as the most likely candidate—an enticing finding, because BMP2 (bone morphogenetic protein 2) is known to be involved in bone development. Sequencing the BMP2 gene in 188 patients and 94 controls to look for functional variants that might account for a predisposition to osteoporosis flagged several possible sequence alterations (which were subsequently shown to be associated with osteoporosis in the larger cohort). Furthermore, an independent replication study with two groups of postmenopausal Danish women—one group with low BMD and one with osteoporotic fractures—found comparable results, with a higher incidence of the BMP2 variants in the affected women compared to the controls. These variants alone can't explain all of the results, however, because a linkage analysis run with patients who do not carry these variants still shows a likely association in the BMP2 region, implying that there may be other variants in BMP2 or adjacent genes that might be influencing osteoporosis.

These results support BMP2 as a likely gene for osteoporosis. Future studies will determine whether it increases risk through its control over peak bone mass, as the researchers suggest, or through some other mechanism. Styrkársdóttir et al. stress that other as-yet-unidentified variants within or near BMP2 may also account for the linkage they found. The researchers hope their work will inspire others to replicate their results, to confirm and elucidate the role of this gene in osteoporosis. Understanding the mechanisms and signaling pathways of BMP2's effects could not only identify drug targets for osteoporosis therapies, but also catch those at high risk before they take that fateful fall.