Low trauma fractures are a major public health problem, especially in the elderly. The most powerful measurable determinant of fracture risk is low bone mass, which is a complex trait with strong genetic determination. Identifying genes underlying variation in bone mass is a critical step towards unraveling functional mutations that cause low bone mass. Extensive regular association studies using unrelated random population samples and a limited few markers have generated controversies for prominent candidate genes studied. Regular linkage studies have been unable to resolve the controversies, largely due to the limited power with insufficient samples. The TDT, while powerful, is a robust approach that can test linkage of candidate genes (particularly those showing significant association) to bone mass. Establishing linkage and robust association is important in identifying genes for bone mass. Screening multiple markers is necessary for testing the significance of candidate genes systematically and exhaustively. We will screen dense (approximately 2kb apart) markers (mainly SNP) in/around 10 prominent candidate genes to test (individual markers and/or haplotypes for closely linked markers in strong linkage disequilibrium) for their association and/or linkage to bone mass variation. Eight hundred nuclear families each consisting of both parents and at least two healthy children will be genotyped. Three hundred ten such families have already been recruited. In addition, we will genotype one microsatellite marker inside or close to each of the 10 candidate genes in 2,886 subjects from 118 pedigrees (recruited already) as well as in the 800 nuclear families. We will use 1) powerful association tests (including those robust ones recently developed) with unrelated samples, 2) robust TDT with nuclear families, and 3) linkage tests in nuclear families and multigeneration pedigrees, to test the significance of these genes for bone mass variation. The study genes or their products have demonstrated biological functional importance in bone metabolism; however, whether or not they are associated with and linked to bone mass variation has not been established. Our proposed study is comprehensive and our statistical genetic analyses show that our study is of very high power and may identify a quantitative trait locus (QTL) with a heritability (h2) as low as 0.05 with a power of > 90%.
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