Genetic Dissection of Femur Breaking Strength in a Large Population (MRL/MpJ×SJL/J) of F2 Mice: Single QTL Effects, Epistasis, and Pleiotropy

Abstract Bone breaking strength is an ultimate measurement of the risk of fracture. For a practical reason, bone mineral density (BMD) has been commonly used for predicting the risk instead. To identify genetic loci influencing femur-breaking strength (FBS), which was measured by three-point bending using an Instron DynaMight Low-Force Testing System, the whole-genome scan was carried out using 119 polymorphic markers in 633 (MRL×SJL) F2 female mice. We identified six significant quantitative trait loci (QTL) affecting bone breaking strength on chromosomes 1, 2, 8, 9, 10, and 17, which together explained 23% of F2 variance. Of those, the QTL on chromosomes 2, 8, and 10 seem to be unique to bone breaking strength, whereas the remaining three QTL are concordant with femur BMD QTL. Genetic analysis suggests that, of these six FBS QTL, three influence BMD, two influence bone quality, and one influences bone size. We detected multiple significant epistatic interactions for FBS, which accounts for half (14.6%) of F2 variance compared with significant single QTL effects. We found evidence that pleiotropic effect might represent a common genetic mechanism to coordinately regulate bone-related phenotypes. Pleiotropic analysis also suggests that our current threshold level for significant QTL may be too high to detect biologically significant QTL with small effect. Together with epistatic interactions, these undetected small QTL could explain 30% of genetic variance that remains unaccounted for in this study (heritability estimate for FBS is 68%). Our findings in single QTL effects, epistasis, and pleiotropy demonstrate that partially overlapped but distinct combinations of genetic loci in MRL/MpJ and SJL/J inbred strains of mice regulate bone strength and bone density. Identification of the genes unique to FBS may have an impact on prediction of osteoporosis in human.