A number sign (#) is used with this entry because of evidence that susceptibility to low bone mineral density is influenced by variation in the LGR4 gene (606666) on chromosome 11p14.

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

By whole-genome sequencing of 2,230 Icelanders, selected for various conditions, Styrkarsdottir et al. (2013) identified a rare nonsense mutation within the LGR4 gene, c.376C-T (606666.0001) that was strongly associated with low BMD and osteoporotic fractures. The strongest site-specific association was with whole-body BMD values (OR = 6.45, p = 5.2 x 10(-8)). Association was also observed with risk of osteoporotic fractures (OR = 3.12, p = 0.00013) and with the BMD definition of osteoporosis (OR = 3.27, p = 0.000050). The association became stronger if a more extreme cutoff was used to define low BMD. Analysis of 5,835 individuals with repeated BMD measurements did not show an association of the 376C-T mutation with age-related changes in BMD, suggesting that the effect of the mutation is to reduce peak bone mass rather than increasing the rate of age-related bone loss. Styrkarsdottir et al. (2013) screened the public Exome Variant Server (EVS) database and directly genotyped the 376C-T variant in 2 sample sets: 3,032 Danish postmenopausal women and 1,393 Australians of northern European descent. Styrkarsdottir et al. (2013) found the 376C-T variant in 1 individual from the Danish sample, who was subsequently shown to be of Icelandic origin. Although the 376C-T mutation seems to be specific to the Icelandic population, Styrkarsdottir et al. (2013) identified 2 frameshift mutations in LGR4 that could mediate similar effects in the EVS database, at a combined frequency similar to that of the 376C-T mutation in Iceland. Neither of these truncating mutations was found in the Danish or Australian sample sets. By haplotype analysis, Styrkarsdottir et al. (2013) estimated that the mutation was introduced into the Icelandic gene pool early in the 17th century.

Styrkarsdottir et al. (2013) investigated the effect of the 376C-T mutation in other human diseases and traits for which genotype and phenotype information was available in the Icelandic population, and identified association with electrolyte imbalance, late onset of menarche, and reduced testosterone levels, as well as increased risk of squamous cell carcinoma of the skin and biliary tract cancer. Styrkarsdottir et al. (2013) concluded that carriers of the LGR4 376C-T mutation are at increased risk of various conditions, similar to the phenotypes observed in Lgr4 mutant mice.