Bone Mineral Density Quantitative Trait Locus 7

For a discussion of genetic heterogeneity of bone mineral density (BMD), see BMND1 (601884).

Mapping

Using an 'affected-only' approach defined by BMD values at both the spine and the hip in combination with osteoporotic fractures, Styrkarsdottir et al. (2003) performed multipoint allele-sharing linkage analysis in 1,323 individuals from 207 extended Icelandic families with osteoporosis and identified linkage to chromosome 20p12.3 (lod score, 5.10; corrected p value = 1.6 x 10(-6)). Fine mapping and haplotype analyses showed the strongest association in the region of the BMP2 gene (112261); sequencing BMP2 in 188 patients and 94 controls revealed a missense polymorphism (S37A) and 2 SNP haplotypes that were associated with osteoporosis (166710). A replication study in postmenopausal Danish women, in one group with persistently low BMD and another with osteoporotic fracture, showed a significant association for haplotype 'C' (p = 0.0038) for low BMD, whereas S37A and haplotype 'B' were nominally significant for osteoporotic fractures and low BMD, respectively.

Kung et al. (2010) performed a genomewide association study in 800 unrelated Southern Chinese women with extreme BMD (high or low), followed by replication studies in 6 independent study populations of European descent and Asian populations involving 18,098 individuals. In the metaanalysis, a SNP (rs2273061) in intron 3 of the JAG1 gene (601920) was associated with high BMD (p = 5.27 x 10(-8) and p = 4.15 x 10(-5) for lumbar spine and femoral neck, respectively) and was further found to be associated with low risk of osteoporotic fracture (p = 0.009; odds ratio, 0.7). Regionwide and haplotype analyses showed that the strongest evidence for association was from a linkage disequilibrium block that included rs2273061 (p = 8.52 x 10(-9) and 3.47 x 10(-5) for lumbar spine and femoral neck, respectively).

Molecular Genetics

Kung et al. (2010) performed functional analysis of the BMD-associated SNP (rs2273061) in intron 3 of the JAG1 gene (601920) using EMSA and observed binding of MYC (190080) to the 'G' but not the 'A' allele; mRNA expression analysis of bone-derived cells and peripheral blood mononuclear cells confirmed association of the high BMD-related G allele with higher JAG1 expression. Kung et al. (2010) concluded that JAG1 is a candidate gene for BMD regulation.