Combination of population and animal studies is a viable approach for genetics of complex traits. We identified several quantitative trait loci (QTL) for osteoporosis-related phenotypes in our studies of both rodents and humans. Some of these QTLs show overlap between mice and humans. The objectives of this proposal thus are: (a) to use information from human genome-wide association study (GWA) to refine a murine model to identify strong candidate genes at the syntenic regions containing QTLs, and (b) to directly incorporate the results of the mouse QTL analysis into a human cohort study. We will focus on QTLs for bone mineral density (BMD) and related traits located on mouse chromosomes 8, 15 and 17, syntenic to human regions on 16q22-q23, 8q24, and 6p21-p12, correspondingly, in which we also found linkage with bone mass related traits in humans. After a QTL gene is identified in the mouse, it will be tested in human association studies. We will examine polymorphisms in humans in a hypothesis- driven association study, which has statistical advantages over association studies that test multiple genes with no a priori hypothesis. The proposed work is innovative since it is based on 2 major developments: (a) novel mouse and human resources that allow in-silico comparative genetic study possible; (b) growing detailed knowledge of inter-species homology between the two species. This study thus has the potential to significantly advance current QTL studies by providing a new set of bioinformatics tools for narrowing QTLs by integrating the analytical strengths of several scientific disciplines. This integrated bioinformatic approach ultimately can be extended to gene identification for other complex diseases. ? ? ?
