We investigate the relevance of the genetic determination of bone mineral density (BMD) variation to that of differential risk to osteoporotic fractures (OF). The high heritability (h2) of BMD and the significant phenotypic correlations between high BMD and low risk to OF are well known. Little is reported on h2 for OF. Extensive molecular genetic studies aimed at uncovering genes for differential risks to OF have focussed on BMD as a surrogate phenotype. However, the relevance of the genetic determination of BMD to that of OF is unknown. This relevance can be characterized by genetic correlation between BMD and OF. For 50 Caucasian pedigrees, we estimated that h2 at the hip is 0.65 (P <0.0001) for BMD and 0.53 (P <0.05) for OF; however, the genetic correlation between BMD and OF is nonsignificant (P > 0.45) and less than 1% of additive genetic variance is shared between them. Hence, most genes found important for BMD may not be relevant to OF at the hip. The phenotypic correlation between high BMD and low risk to OF at the hip (approximately -0.30) is largely due to an environmental correlation (ρE = -0.73, P <0.0001). The search for genes for OF should start with a significant h2 for OF and should include risk factors (besides BMD) that are genetically correlated with OF. All genes found important for various risk factors must be tested for their relevance to OF. Ideally, employing OF per se as a direct phenotype for gene hunting and testing can ensure the importance and direct relevance of the genes found for the risk of OF. This study may have significant implications for the common practice of gene search for complex diseases through underlying risk factors (usually quantitative traits).
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