BONE QUALITY: A COMPOSITE OF COMPLEX PHENOTYPIC TRAITS

Osteoporosis, skeletal fragility, and fracture are well-known pathological conditions associated with aging. The ability of bone to resist fracture, i.e. bone quality, can be viewed as a composite of phenotypic traits, each under polygenic and environmental regulation. The principal aim of this study is to positively identify chromosomal regions (termed quantitative trait loci or QTLs) that contain genes influencing bone quality across the lifespan. The long-term goal is to elucidate the causal fields created by genes, environment, gene-gene, and gene-environment interactions that ultimately dictate the quality of our bones in old age. Phenotypic traits encompassing bone morphology, composition, and mechanical performance will be assessed in two types of descendents from crosses of C57BL/6 (B6) and DBN2J (D2) inbred strains of mice: a) a BXD F2 intercross, and b) twenty-two different BXD recombinant inbred (RI) strains. Traits related to muscle mass, activity, and general health will also be quantitatively measured. Over twenty-five hundred animals, equally divided between male and female, will be examined at three ages representative of young adulthood (150 days), midlife (450 days), and advanced age (750 days). Quantitative bone quality data will be analyzed against corresponding genetic marker information from each individual F2 animal and from pre-existing RI databases. Univariate screening will be used to conduct genome-wide scans for QTLs associated with bone quality and potentially useful marker arrays correlating with distinct skeletal phenotypes will be identified. Regressions will be performed between skeletal phenotypes and phenotypes from other domains to determine relationships across physiologic systems and multivariate analyses will be conducted to identify QTLs that have pleiotropic effects on the correlated phenotypes. QTLs strongly associated with age-related reductions in bone quality will be sought by deriving novel phenotypes of bone loss from the longitudinal data.