Genetics of Bone Mineral Density: Evidence for a Major Pleiotropic Effect From an Intercontinental Study

Abstract

BMD is a primary predictor of osteoporotic fracture, and its genetic determination is still unclear. This study showed that the correlation between BMD at different skeletal sites is caused by an underlying genetic structure of common genetic effects. In addition to possible shared (pleiotropic) genetic and environmental effects, each of the BMD variables may also be determined by site-specific genetic factors.Introduction: BMD is a primary predictor of osteoporotic fracture and a key phenotype for the genetic study of osteoporosis. The interindividual variation in BMD measured at a given skeletal site is largely regulated by genetic factors. A strong phenotypic covariation exists for BMD at different skeletal sites. This study tests the hypothesis that the covariation is in fact caused by an underlying genetic structure of common genetic effects and that, in addition to possible shared (pleiotropic) genetic effects, each of the BMD variables may also be determined by site-specific genetic factors Materials and Methods: A bivariate complex segregation analysis as implemented in statistical package PAP was conducted to explore various models of pleiotropic genetic and environmental transmission in lumbar spine and femoral neck BMD, as well as in compact and spongious segments of hand phalanges. The BMD was obtained in three ethnically, culturally, and socially heterogeneous samples of white pedigrees, with 2549 individuals between 18 and 100 years of age, from Australia, Europe, and North America. Results and Conclusions:The genetic correlation between BMD measures ranged between 0.50 Ϯ 0.09 and 0.79 Ϯ 0.04 in the three samples. In each sample, the model incorporated a major locus pleiotropic effect, and residual correlation was found to be the most parsimonious model. Estimated parameters from the model indicated a significant pleiotropic major gene effect on both lumbar spine and femoral neck BMD, with the existence of a significant residual correlation (0.51 Ϯ 0.07 to 0.66 Ϯ 0.04). These results suggest that the covariation in BMD at different skeletal sites, and between mostly compact versus mostly trabecular bone, was largely determined by common genetic factors that are pleiotropic or in close linkage and linkage disequilibirum, while at the same time, exhibiting considerable evidence of shared environmental effects. The results, for the first time, suggest that the possibility of pleiotropic genetic effect may be controlled by a major genetic locus. Identification of the major locus could open new opportunity to understanding the liability and pathogenic processes in which they are involved in the determination of fracture risk.

Univariate and bivariate variance component linkage analysis of a whole-genome scan for loci contributing to bone mineral density

“…Bivariate linkage analysis has been shown to have increased power over univariate analysis in detecting genes of pleiotropic effect. 16 A significant pleiotropic effect on LS and FN BMD was estimated in a large sample from an intercontinental study, 28 and our own quantitative analysis showed that the genetic correlations at all three pairs of skeletal sites are significantly different from 0 (Table 1). Others 10,29 have used principal component analysis to test for common QTLs underlying bone mass at different skeletal sites.…”

A Differential Association of ALOX15 Polymorphisms with Bone Mineral Density in Pre- and Post-Menopausal Women

“…The association of different haplotypes with different skeletal sites, and also the observation of an opposite effect in pre-and post-menopausal women suggest that the effect of ALOX15 is site dependent and menopausal-status dependent [2] . This finding supports that of our recent study wherein the linkage of quantitative trait locus with BMD variation was site-specific and menopause status-specific [28] .…”

“…Among the various parameters that contribute to bone strength, bone mineral density (BMD) is one of the best predictors of fracture risk and the most well described. Numerous twin and family studies suggest that BMD, bone mineral content (BMC) and bone area are to a great extent genetically determined [1][2][3][4][5][6] .…”

Bivariate association analysis in selected samples: application to a GWAS of two bone mineral density phenotypes in males with high or low BMD

“…As a strong (B0.5) and positive phenotypic covariation exists for BMD values at the LS and at the FN, 23 we generated data for two positively correlated quantitative phenotypes. Further, in real data sets, as causal loci usually contribute a small proportion to the total phenotypic correlation, residual correlation approximates phenotypic correlation between traits.…”