Linkage of Osteoporosis to Chromosome 20p12 and Association to BMP2

Abstract

Osteoporotic fractures are a major cause of morbidity and mortality in ageing populations. Osteoporosis, defined as low bone mineral density (BMD) and associated fractures, have significant genetic components that are largely unknown. Linkage analysis in a large number of extended osteoporosis families in Iceland, using a phenotype that combines osteoporotic fractures and BMD measurements, showed linkage to Chromosome 20p12.3 (multipoint allele-sharing LOD, 5.10; p value, 6.3 × 10−7), results that are statistically significant after adjusting for the number of phenotypes tested and the genome-wide search. A follow-up association analysis using closely spaced polymorphic markers was performed. Three variants in the bone morphogenetic protein 2 (BMP2) gene, a missense polymorphism and two anonymous single nucleotide polymorphism haplotypes, were determined to be associated with osteoporosis in the Icelandic patients. The association is seen with many definitions of an osteoporotic phenotype, including osteoporotic fractures as well as low BMD, both before and after menopause. A replication study with a Danish cohort of postmenopausal women was conducted to confirm the contribution of the three identified variants. In conclusion, we find that a region on the short arm of Chromosome 20 contains a gene or genes that appear to be a major risk factor for osteoporosis and osteoporotic fractures, and our evidence supports the view that BMP2 is at least one of these genes.

Calcium Phosphate Cement with BMP-2-loaded Gelatin Microspheres Enhances Bone Healing in Osteoporosis: A Pilot Study

“…BMP-2 plays an important role in osteoporosis. Variants of the BMP-2 genes are associated with familial osteoporosis, and rhBMP-2 can reverse bone loss in osteopenic mice [31,32]. Controlled release of rhBMP-2 can be obtained easily when the protein is mixed with CPC during cement setting, and rhBMP-2/CPC is effective in bridging critical-sized bone defects without osteoporosis [4,11,28].…”

The use of pedigree, sib-pair and association studies of common diseases for genetic mapping and epidemiology

“…In the past few years it became feasible to genotype cheaply large pedigrees with much greater numbers of microsatellites than were previously used for genome scans, and statistical programs that are now available permit efficient computation of linkage even in complex pedigrees 28,29 . These advances allowed a substantial increase in the scale of pedigree-based linkage studies 2,4,[30][31][32][33][34][35][36][37][38] . Inadequate technology and statistical methodology have similarly hindered implementation of alternatives to pedigreebased mapping.…”

“…Pedigree studies of common forms of these diseases have led to positional candidate association studies that have provided intriguing, but mainly statistically equivocal, evidence for variants that may have a role in disease susceptibility; variants identified so far do not have the biological effects of most mutations underlying mendelian disorders [2][3][4][5]79 . In this respect, the field is eagerly awaiting the results of fine-mapping studies for several diseases being undertaken by deCODE and others.…”

“…1). deCODE Genetics, a company attempting to identify comprehensively the genetic contributions to common diseases in Iceland, has reported candidate genes for underlying susceptibility to several diseases [2][3][4][5] . Considering the far more numerous publications describing negative or equivocal findings, it is uncertain how we should assess the current state of common-trait genetics.…”

Genetics of osteoporosis

“…The most important quantitative trait loci (QTL) for BMD identified by these studies are summarised in Table 1. Few of the genome-wide scans so far performed have identified QTL that meet the criteria for genome-wide significance, and only one gene that regulates susceptibility to osteoporosis has been identified by this approach; the BMP2 gene that encodes bone morphogenic protein 2, an important regulator of osteoblast differentiation (Styrkarsdottir et al 2003). Several important findings have emerged from these studies.…”