Femur mechanical properties in the F2 progeny of an NZB/B1NJ × RF/J cross are regulated predominantly by genetic loci that regulate bone geometry

Genetic analysis of an NZB/B1NJ × RF/J cross has identified QTLs for femur mechanical, geometric, and densitometric phenotypes. Most mechanical QTLs were associated with geometric QTLs, strongly suggesting common genetic regulation. Introduction: Previous studies have shown that bone architecture and BMD are important factors affecting bone strength, and both are genetically regulated. We conducted genetic analyses for loci regulating femur mechanical properties, geometric properties, and BMD in a cohort of F₂ mice derived from intercross matings of (NZB/B1NJ × RF/J)F₁ parents. Materials and Methods: Femurs were isolated from 662 10-week-old females. Mechanical properties were determined for a femur from each animal by three-point bending. Geometric properties and volumetric BMD (vBMD) were determined by pQCT. Genotype data were obtained by PCR assays for polymorphic markers carried in the genomic DNA of each mouse. Genome-wide scans were carried out for co-segregation of genetic marker data with values from 23 different phenotypes. Quantitative trait loci (QTLs) were identified for mechanical, geometric, and mineral density phenotypes. Results: QTLs for many phenotypes were significantly refined by covariate analyses using body weight and femur length. Major QTLs for mechanical and geometric phenotypes were found on chromosomes 5, 7, 9, 11, and 12. Nine chromosomal locations were identified with mechanical QTLs and 17 locations with one or more geometric QTLs. The significance of five mechanical and nine geometric QTLs was affected by the inclusion of covariates. These changes included both decreases and increases in significance. The QTLs on chromosomes 5 and 12 were decreased by inclusion of the covariates in the analysis, but QTLs on 7 and 11 were unaffected. Mechanical QTLs were almost always associated with geometric QTLs and less commonly (two of six) with vBMD QTLs. Conclusions: Genetic regulation of mechanical properties in the F₂ mice of this NZB/B1NJ × RF/J cross seems to be caused by genes regulating femur geometry.