Quantitative trait loci for femoral and lumbar vertebral bone mineral density in C57BL/6J and C3H/HeJ inbred strains of mice

Wg. Beamer et al., Quantitative trait loci for femoral and lumbar vertebral bone mineral density in C57BL/6J and C3H/HeJ inbred strains of mice, J BONE MIN, 16(7), 2001, pp. 1195-1206
Citations number
Categorie Soggetti
Endocrinology, Nutrition & Metabolism
Journal title
ISSN journal
0884-0431 → ACNP
Year of publication
1195 - 1206
SICI code
Significant differences in vertebral (9%) and femoral(50%) adult bone miner al density (BMD) between the C57BL/6J (B6) and C3/HeJ (C3H) inbred strains of mice have been subjected to genetic analyses for quantitative trait loci (QTL). Nine hundred eighty-six B6C3F2 females were analyzed to gain insigh t into the number of genes that regulate peak BMD and their locations. Femu rs and lumbar vertebrae were isolated from it-month-old B6C3F2 females at s keletal maturity and then BMD was determined by peripheral quantitative com puted tomography (pQCT). Estimates of BMD heritability were 83% for femurs and 72% for vertebrae. Genomic DNA from F2 progeny was screened for 107 pol ymerase chain reaction (PCR)-based markers discriminating B6 and C3H allele s on ah 19 autosomes. The regression analyses of markers on BMD revealed te n chromosomes (1, 2, 4, 6, 11, 12, 13, 14, 16,and 18) carrying QTLs for fem urs and seven chromosomes (1, 4, 7, 9, 11, 14, and 18) carrying QTLs for ve rtebrae, each with log(10) of the odds ratio (LOD) scores of 2.8 or better. The QTLs on chromosomes (Chrs) 2, 6, 12, 13, and 16 were unique to femurs, whereas the QTLs on Chrs 7 and 9 were unique to vertebrae. When the two bo ne sites had a QTL on the same chromosome, the same marker had the highest, although different, LOD score. A pairwise comparison by analysis of varian ce (ANOVA) did not reveal significant gene x gene interactions between QTLs for either bone site. BMD variance accounted for by individual QTLs ranged from 1% to 10%. Collectively, the BMD QTLs for femurs accounted for 35.1% and for vertebrae accounted for 23.7% of the F2 population variances in the se bones. When mice were homozygous c3/c3 in the QTL region, 8 of the 10 QT Ls increased, while the remaining two QTLs on Chrs 6 and 12 decreased, femo ral BMD. Similarly, when mice were homozygous c3/c3 in the QTL region for t he vertebrae, five of the seven QTLs increased, while two QTLs on Chrs 7 an d 9 decreased, BMD. These findings show the genetic complexity of BMD with multiple genes participating in its regulation. Although 5 of the 12 QTLs a re considered to be skeleton-wide loci and commonly affect both femurs and vertebrae, each of the bone sites also exhibited unique QTLs. Thus, the BMD phenotype can be partitioned into its genetic components and the effects o f these loci on normal bone biology can be determined. Importantly, the BMD QTLs that we have identified are in regions of the mouse genome that have known human homology, and the QTLs will become useful experimental tools fo r mechanistic and therapeutic analyses of bone regulatory genes.