GENETICS OF SEX EFFECTS ON BONE DENSITY AND TURNOVER

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Osteoporosis and associated skeletal fragility are paramount public health concerns, affecting 10.1 million individuals, 77% of whom are women. The need to understand the biological mechanisms producing this complex phenotype and this sex difference is immediate. Low bone mass, the most reliable indicator of osteoporosis susceptibility, results from complex interactions between genes and environment. Areal bone mineral density (aBMD) provides a measure of current skeletal mass, while serum measures of bone turnover reflect the degree of bone formation and resorption occurring in an individual at any one time. aBMD and biochemical markers of bone turnover, used alone and together, are effective predictors of fracture risk. Studies consistently show strong genetic effects on these phenotypes. Identifying chromosomal regions harboring genes responsible for these effects, and understanding relevant genotype-by-environment (GxE) interactions are essential for the development of protocols to identify individuals at greatest risk for fracture who might benefit most from early intervention. The overall aim of this research is to detect and characterize effects of interactions between genotype and ¿sex, -age, and ¿reproductive history on BMD and bone turnover in pedigreed of baboons. Data include measures of BMD, serum markers of bone turnover, clinical and reproductive histories, genotypes at 331 highly polymorphic microsatellite marker loci, and a baboon whole genome linkage map. The specific aims of this research are to: 1) detect and characterize the effects of sex, age, and female reproductive history variables on the phenotypic variance in area BMD and serum measures of bone turnover; 2) Quantify the effects of genotype-by-sex, genotype-by-age, and genotype-by-reproductive history variable interactions on normal quantitative variation n aBMD and serum measures of bone turnover, and 3) (a) assess the effects of bone-related quantitative trait loci (QTLs), previously localized in these baboons, on detected GxE interactions and (b) conduct whole genome linkage screens to localize new QTLs responsible for detected GxE effects.