Chromosomal mapping of osteopenia-associated quantitative trait loci usingclosely related mouse strains

Peak bone mineral density (BMD) is a highly heritable trait in humans and i s currently the best predictor of skeletal fragility underlying osteoporosi s. The SAMP6 mouse strain displays unusually low BMD at maturity, and age-d ependent osteopenia associated with defective osteoblastogenesis. To identi fy quantitative trait loci (QTLs) influencing bone density, we constructed crosses between SAMP6 and either AKR/J or SAMP6, two related mouse strains of higher peak BMD. Due to common ancestry of these strains, intercross par ents differed at only 39-40% of 227 highly-polymorphic genotyping markers, thus restricting our search to this informative portion of the genome and r educing the number of mice required for QTL significance. Using dual energy X-ray absorptiometry (DEXA), we measured spinal BMD in F-2 cross progeny a t 4 months of age, and selectively genotyped those in the highest and lowes t quartiles for BMD. Based on linear regression of bone density on genotype , including Composite Interval Mapping to enhance mapping precision while a djusting for effects of distal markers, me identified multiple QTLs signifi cantly affecting spinal BMD; these were mapped to regions of chromosomes 2 (two sites, one confirmed in both crosses), 7, 11, 13 and 16, One of these loci Had been previously identified as a significant bone-density QTL, whil e 3 substantiate QTLs suggested by a low-power study of 24 recombinant-inbr ed mouse lines. Such recurrent appearance of QTLs, especially in crosses in volving distantly-related strains, implies that polymorphism at these loci may be favored by evolution and might underlie variation in peak bone densi ty among humans.