The proposed study is submitted in response to program announcement PA-02-110, """"""""Genetic Architecture, Biological Variation and Complex Phenotypes"""""""". Osteoporosis is a disease of aging characterized by low bone mass and structural deterioration of bone tissue, leading to bone fragility and an increased susceptibility to fractures (NIH Consensus Statement, 2000). Today, osteoporosis is the most prevalent metabolic bone disease in the United States with nearly 10 million people afflicted and another 34 million at risk. In recent years there has been considerable interest in understanding the complex genetic basis of osteoporosis risk. Despite our increasing knowledge of the genetics of osteoporosis risk, identifying the specific polymorphisms involved has continued to be an elusive goal. Traditionally, the most widely used measure in the assessment of osteoporosis risk is bone mineral density (BMD) because of its high correlation with fracture risk. In addition to BMD, aspects of bone quality are also important predictors of fracture risk;these measures include rate of bone turnover as well as characteristics of bone architecture. Some of these traits are likely to share common genetic pathways. The proposed study investigates the genetic determinants of BMD and measures of bone quality in a sample of 2,000 adults from large extended pedigrees. The main goal of the proposed study is the identification of genes influencing BMD and measures of bone quality, as well as the identification of genes that have joint influences on these traits. Specifically, we will: 1) determine the extent to which genetic and specific environmental factors influence variation in BMD and measures of bone quality;2) identify chromosomal regions harboring genes influencing BMD and measures of bone quality using quantitative trait linkage analysis. Additionally, we will identify chromosomal regions with joint influences on BMD and measures of bone quality using multivariate quantitative trait linkage analysis;and 3) fine map the regions surrounding the five most promising QTL identified through quantitative trait linkage analysis. The results of this proposed study characterizing, quantifying, and localizing genetic effects on BMD and measures of bone quality will provide important findings for subsequent research aimed at the identification of the true functional polymorphisms influencing BMD and subsequent osteoporosis risk. Furthermore, these findings will have the potential to lead to new developments in the assessment of risk, prevention, and treatment of osteoporosis.
