A novel locus on the X chromosome regulates post-maturity bone density changes in mice

Two mouse strains, AKR/J and SAMP6, were assessed longitudinally for bone mineral density of the spine. They displayed very different time courses of bone accrual, with the SAMP6 strain reaching a plateau for vertebral BMD at 3 months, whereas AKR/J mice continued to increase spine BMD for at least 8 months. Among 253 F2 progeny of an AKR/J × SAMP6 cross, at 4 months of age, the BMD variance was 5-6% of the mean, vs. 15% for weight. Variance increased with age for every parameter measured, and was generally higher among males. The ratio of 6-month/4-month spine BMDs, termed ΔsBMD, had a normal distribution with 5.7% variance, and was largely independent of spine BMD (R = − 0.23) or body weight (R = − 0.12) at maturity. Heritability of the ΔsBMD trait was calculated at 0.59. Genetic mapping identified two significant loci, both distinct from those observed for BMD at maturity-implying that different genes regulate skeletal growth vs. remodeling. A locus on the X chromosome, replicated in two mouse F2 populations (P < 10− 4 for combined discovery and confirmation), affects age-dependent BMD change for both spine and the full skeleton. Its position agrees with a very narrow region identified by association mapping for effects on lumbar bone density in postmenopausal women [Parsons CA, Mroczkowski HJ, McGuigan FE, Albagha OM, Manolagas S, Reid DM, et al. Interspecies synteny mapping identifies a quantitative trait locus for bone mineral density on human chromosome Xp22. Hum Mol Genet 2005;14:3141-8]. A second locus, on chromosome 7, was observed in only one cross. Single-nucleotide polymorphisms (SNPs) are highly clustered near these loci, distinguishing the parental strains over only limited spans.