Pleiotropy and heterogeneity in the expression of bone strength-related phenotypes in extended pedigrees

Abstract

Genetic analysis in 3535 relative pairs from extended multigenerational families of African heritage showed that volumetric BMD is a highly heritable polygenic trait that is under compartment-specific genetic regulation. The majority of the phenotypic variation in bone size and volumetric BMD also seems to be strongly influenced by distinct genes for each trait. Introduction: BMD and bone size contribute to bone strength and the risk of fracture. Little is known about the genetic architecture of QCT measures of volumetric BMD and bone size. We studied the contribution of genes, shared genes (pleiotropy), and shared environment to cortical and trabecular volumetric BMD and bone size using variance components analysis. Materials and Methods: A total of 471 individuals ≥18 yr of age (mean, 43 yr) from eight multigenerational Afro-Caribbean families (mean family size > 50; 3535 relative pairs) underwent a peripheral QCT scan of the radius and tibia and anthropometry. Results: Strong positive genetic correlations were observed for trabecular or cortical BMD measured at the tibia and radius (ρG > 0.82, p < 0.01), but not between trabecular and cortical BMD measured within the same anatomical site. Genetic correlations between volumetric BMD and bone length and circumference were also not statistically significant. Conclusions: BMD is a highly heritable polygenic trait that is under compartment-specific genetic regulation. The majority of the phenotypic variation in skeletal size and density seems to be strongly influenced by distinct sets of genes for each trait. © 2007 American Society for Bone and Mineral Research.