QUANTITATIVE TRAIT LOCI AFFECTING PEAK BONE-MINERAL DENSITY IN MICE

Peak bone mass is a major determinant of risk of osteoporotic fracture . Family and twin studies have found a strong genetic component to the determination of bone mineral density (BMD). Ho However, BMD is a com plex trait whose expression is confounded by environmental influences and polygenic inheritance, The number, locations, and effects of the i ndividual genes contributing to natural variation in this trait are al l unknown. Experimental animal models provide a means to circumvent co mplicating environmental factors, and the development of dense genetic maps based on molecular markers now provides opportunities to resolve quantitative genetic variation into individual regions of the genome influencing a given trait (quantitative trait loci, QTL), To begin to identify the heritable determinants of BMD, we have examined genetical ly distinct laboratory mouse strains raised under strict environmental control, Mouse whole-body bone mineral content by dual-energy X-ray a bsorptiometry (DXA) correlated strongly with skeletal calcium content by ashing, and peak whole-body BMD by DXA in female mice occurred at s imilar to 80-90 days of age, We therefore determined mean body weight and peak whole body BMD values in 12-week-old female mice from a panel of 24 recombinant inbred (RI) BXD strains, derived from a cross betwe en C57BL/6 and DBA/2 progenitors, The distribution of body weight and BMD values among the strains clearly indicated the presence of strong genetic influences on both of these traits, with an estimated narrow s ense heritability of 60% and 35%, respectively, The patterns of differ ences in body weight and peak whole body BMD in the BXD strains were t hen integrated with a large database of genetic markers preciously def ined in the RI BXD strains to generate chromosome map sites for QTL. A fter correction for redundancy among the significant correlations, QTL analysis of the BXD RT strain series provisionally identified 10 chro mosomal sites linked to peak bone mass development in the female, Seve ral of the identified sites map near genes encoding hormones, structur al proteins, and cell surface receptors that are intricately involved in skeletal homeostasis, Four QTL for body weight were also identified , One of these loci was also strongly linked to inherited variation in BMD. This finding suggests that body weight and peak BMD may be influ enced by linked genes or perhaps by common genes with pleiotropic effe cts, Our phenotyping in the RI BXD strains has allowed us to map a num ber of specific genetic loci strongly related to the acquisition of pe ak BMD, Confirmation of these findings nili likely result in the under standing of which genes control skeletal health.