Bone Mineral Density Quantitative Trait Locus 1

A number sign (#) is used with this entry because bone mineral density variation (BMND1) can result from mutation in the LRP5 gene (603506) on chromosome 11q13. The variation includes an isolated high bone mass trait, the osteoporosis-pseudoglioma syndrome (OPPG; 259770), and low bone mineral density leading to osteoporosis (see 166710).

BMND12 (612560) is associated with copy number variation of the UGT2B17 gene (601903) on chromosome 4q13.2. BMND15 (613418) is associated with mutation in the MIR2861 gene (613405) on chromosome 9q34.11. BMND16 (615221) is associated with mutation in the WNT1 gene (164820) on chromosome 12q13. BMND17 (615311) is associated with mutation in the GPR48 gene (606666) on chromosome 11p14.1. BNMD18 is associated with mutation in the PLS3 gene (300131) on chromosome Xq23.

Other loci involved in bone mineral density variation include BMND2 (605833) on chromosome 1q21-q23, BMND3 (606928) on chromosome 1p36, BMND4 (300536) on chromosome Xq27, BMND5 (609354) on chromosome 11q23, BMND6 (609876) on chromosome 21q22-qter, BMND7 (611738) on chromosome 20p12, BMND8 (611739) on chromosome 11p12, BMND9 (612110) on chromosome 13q14, BMND10 (612113) on chromosome 8q24, BMND11 (612114) on chromosome 6q25, BMND13 (612727) on chromosome 16q23, and BMND14 (612728) on chromosome 1p33-p32.

See also STQTL3 (606257) for discussion of a locus associated with bone mineral density and growth in childhood.

Clinical Features

Johnson et al. (1997) described a family with very high spinal bone mineral density, the so-called spinal Z(BMD). In this kindred, the spinal Z(BMD) was 5.54 in 12 affected individuals and 0.41 in 16 unaffected individuals. The affected individuals had a normal skeletal structure and no other unusual clinical findings. In an accompanying editorial to the report of Johnson et al. (1997), Whyte (1997) noted that high bone mass can result from osteosclerosis and/or hyperostosis occurring focally or throughout the skeleton. Whyte (1997) pointed out that the term osteosclerosis refers to increased density of trabecular (spongy) bone, whereas hyperostosis refers to thickening of cortical (compact) bone from deposition of osseous tissue along subperiosteal and/or endosteal surfaces. According to Whyte (1997), there are at least 20 well-recognized, although rare, genetic causes of increased skeletal mass.

Inheritance

To estimate the heritability and possible pattern of inheritance of each measure of BMD and a BMD/bone mineral content (BMC) common general component, Nguyen et al. (2003) measured BMD and BMC at the lumbar spine and femoral neck in 330 men and 413 women, aged 18 to 90 years, from 107 nuclear and complex families. After adjusting for age and body weight, familial factors accounted for up to 72% of the total variation in BMD. Complex segregation analysis provided evidence that a putative major gene codominant model best explains the inheritance pattern for BMD, and suggested that a codominant major gene model best explains the inheritance pattern for BMD/BMC.

Population Genetics

BMD and fracture rates vary among women of differing ethnicities. Most reports had suggested that BMD is highest in African Americans, lowest in Asians, and intermediate in Caucasians, yet Asians have lower fracture rates than Caucasians. Finkelstein et al. (2002) assessed lumbar spine and femoral neck BMD by dual-energy x-ray absorptiometry in 2,277 (for the lumbar spine) and 2,330 (for the femoral neck) premenopausal or early perimenopausal women participating in the Study of Women's Health Across the Nation (SWAN). BMDs were compared among ethnic groups before and after adjustment for covariates. Before adjustment, lumbar spine and femoral neck BMDs were highest in African American women, next highest in Caucasian women, and lowest in Chinese and Japanese women. Unadjusted lumbar spine and femoral neck BMDs were 7 to 12% and 14 to 24% higher, respectively, in African American women than in Caucasians, Japanese, or Chinese women. After adjustment, lumbar spine and femoral neck BMD remained highest in African American women, and there were no significant differences between the remaining groups. When BMD was assessed in a subset of women weighing less than 70 kg and then adjusted for covariates, lumbar spine BMD became similar in African American, Chinese, and Japanese women and was lowest in Caucasian women. Finkelstein et al. (2002) concluded that femoral neck BMD is highest in African Americans and similar in Chinese, Japanese, and Caucasians. They also suggested that these findings may explain why Caucasian women have higher fracture rates than African Americans and Asians.

Mapping

In a family in which several members had high bone mineral density, normal skeletal structure, and no other unusual clinical findings, Johnson et al. (1997) found linkage of the trait to markers on 11q12-q13. The highest lod score (5.21), obtained in 2-point analysis when a quantitative trait model was used, was at D11S987. Johnson et al. (1997) pointed out that the OPPG syndrome maps to the same area and suggested that they may be allelic disorders.

By extending the pedigree studied by Johnson et al. (1997) and genotyping additional markers, Little et al. (2002) refined the critical interval to a 3-cM region between markers D11S987 and GTC271K22.

Koller et al. (1998) noted that autosomal recessive osteopetrosis also maps to 11q12-q13 and evaluated that chromosomal region for evidence of a quantitative trait locus contributing to variation in BMD in the normal population. In a linkage study of a sample of 835 premenopausal Caucasian and African American sisters, they found a maximum multipoint lod score of 3.50 with femoral neck BMD near marker D11S987, which maps to 11q12-q13. Thus, the gene responsible for one or more of the rare mendelian BMD traits linked to 11q12-q13 may play an important role in osteoporosis in the general population.

Deng et al. (2001) genotyped 5 markers in a genomic region of approximately 27 cM centering on D11S987 and measured BMD and other traits (weight, etc.) for 635 individuals from 53 pedigrees. Each of these pedigrees was ascertained through a proband with BMD Z scores less than -1.28 at the hip or spine. The maximum lod score at D11S987 was 0.15. They concluded that there was no evidence for linkage of the marker D11S987 on human chromosome 11q12-q13 to BMD variation in their study population.

Molecular Genetics

In a family with high bone mass linked to chromosome 11q13 (Johnson et al., 1997), Little et al. (2002) identified a mutation in the LRP5 gene (603506.0013). Boyden et al. (2002) identified the same mutation in affected members of a family with an autosomal dominant syndrome characterized by high bone mass, wide and deep mandible, and torus palatinus.

Mizuguchi et al. (2004) performed an association study between bone mineral density and 9 candidate genes in 481 healthy Japanese women. They found that only LRP5 showed a significant association with BMD. A follow-up case-control study of 126 women with osteoporosis (see 166710) and 131 normal controls revealed a significant difference in allelic frequency of the LRP5 2220C-T SNP (603506.0019) (p = 0.009). The authors suggested that LRP5 is a BMD determinant and contributes to a risk of osteoporosis.

History

Morrison et al. (1994) reported linkage and association between a polymorphism in the vitamin D receptor (601769) on chromosome 12q12 and BMD at the spine; however, Hustmyer et al. (1994) and Peacock et al. (1995) failed to replicate these findings. A metaanalysis by Cooper and Umbach (1996), involving data from 16 studies, found no significant association between the vitamin D receptor locus and bone density when the data of Morrison et al. (1994), which had been partially retracted, were excluded from the analysis.