Abstract
Osteoporosis is a major public health problem, mainly characterized by compromised bone strength. The bone strength is determined by many skeletal factors, including bone mineral density (BMD), geometric structure, microarchitecture, and intrinsic material properties. The BMD and geometric structure have been demonstrated to be under strong genetic controls. Identification of genetic determinants for these skeletal factors will lead to a better understanding of osteoporosis pathophysiology and to the development of new diagnostic tools and therapeutic agents. A large number of linkage and association studies have been conducted on BMD and several on bone geometry, however, relatively little success has been achieved and inconsistent results have accumulated. Though the lack of inconsistence may be due to a number of factors, one of the main reasons is that most of the previous studies are lack of sufficient statistical power to generate reliable and reproducible results. Therefore, in the present project, I onducted powerful genome-wide linkage scans for areal BMD, areal bone size, and femoral neck cross-sectional geometry in a sample of 79 multigenerational Caucasian pedigrees. Several promising genomic regions have been identified for various skeletal traits. For instance, genomic regions at llq23, 20pl2-ql2 and on chromosome X may contain genes influencing BMD variation. In addition, the regions on 20pl2-ql2 and chromosome X also showed linkage evidence for several femoral neck cross-sectional geometric variables, suggesting that these potential quantitative trait loci (QTLs) may regulate bone geometric structure as well. Moreover, gender-specific linkage analyses suggested that some of these QTLs may affect these bone phenotypes in a sex-specific manner.The significance of these regions was further corroborated by earlier findings or by the candidate genes within the regions. Further explorations of these regions are warranted. I also identified significant/suggestive linkage evidences at several other genomic regions, such as 3p26 for spine BMD, 15q23 for hip BMD, 14qll for hip bone size, and 8q24 and 10q26 for femoral neck cross-sectional geometry. Together with the findings from other studies, the current study has further delineated the genetic basis of several osteoporosis-related skeletal traits and highlighted the importance of increasing sample size to confirm linkage findings and to identify new regions of linkage.