Assessment of linkage and association of 13 genetic loci with bone mineral density

Bone mineral density (BMD), an important risk factor for osteoporosis, is a complex trait likely affected by multiple genes. The linkage and/or association of 13 polymorphic loci of seven candidate genes (estrogen receptor alpha [ER alpha] and beta [ER beta], calcium-sensing receptor, vitamin D receptor, collagen type 1 alpha 1, low-density lipoprotein [LDL] receptor-related protein 5 [LRPS], and transforming growth factor beta 1) were evaluated in 177 southern Chinese pedigrees of 674 subjects, with each pedigree identified through a proband having a BMD Z score of -1.28 or less at the hip or spine. A suggestive linkage was detected between the IVS1-351A/G polymorphism of ER alpha and spine BMD, and between the 1082G/A, 1730G/A, and D14S1026 polymorphisms of ER beta and BMD at both spine and hip. The quantitative transmission disequilibrium test (QTDT) detected total family association between 1730G/A of ER beta and BMD at spine and hip; between D14S1026 of ER beta and hip BMD; and between the 266A/G and 2220C/T polymorphisms of LRP5 and hip BMD. Similar total family associations were detected when only the females were analyzed. In addition, the IVS1-397T/C polymorphism of ER alpha was associated with spine BMD, and the 266A/G and 2220C/T polymorphisms of LRP5 were associated with femoral neck BMD in the females. A within-family association was detected with the IVS1-397T/C polymorphism of ER alpha, and the 266A/G and 2220C/T polymorphisms of LRP5 in the females. The effect of each polymorphism on BMD variance ranged from 1% to 4%. In conclusion, ER alpha, ER beta and LRP5 are important candidate genes determining BMD variation, especially in females.