Test of linkage and association of 14 genetic loci with bone size

Abstract

Bone size is an important independent contributor to bone strength, a determinant of osteoporotic fracture. To evaluate the genetic determinants of bone size, linkage and/or association of 14 polymorphic loci of 8 candidate genes were studied in 177 southern Chinese pedigrees of 674 subjects (567 females and 107 males). Four skeletal sites were studied, including the LI-4 lumbar spine, trochanter, femoral neck and total hip region. Age, sex, height and weight were included as covariates in the analysis. The candidate genes studied include estrogen receptor alpha (ERα) and beta (ERβ), calcium sensing receptor (CASR), vitamin D receptor (VDR), collagen type Iα1 (COLIA1), LDL receptor-related protein 5 (LRP5), transforming growth factor β1 (TGF β), and parathyroid hormone receptor 1 (PTHR1). Multi-point variance component linkage analysis was performed using the MERLIN program. Linkage was observed between D14S1026 genotypes of ERβ with total hip area; CASR genotypes with femoral neck bone area; 266A/G, 2220C/T and 3989C/T genotypes of LRP5 with total hip bone area. Association of bone size was determined using the quantitative transmission disequilibrium test (QTDT). After covariates adjustment, total family association revealed significant association of D14S1026 genotypes of ERβ with spine, trochanter and total hip bone area; D3S1289 genotypes with femoral neck, trochanter and hip region bone area; and CASR genotype with femoral neck and total hip bone area. These results were also seen when only the females were studied. In addition, 2T/C of VDR was associated with spine bone area in all subjects while 266A/G of LRP5 was associated with total hip bone area when the females were analysed separately. When all subjects were analysed, significant within-family association was detected between D14S1026 genotypes of ERβ with spine bone area. Overall, these data suggested ERβ, CASR and LRP5 are important candidate genes for determining bone size variation. In addition, VDR gene and D3S1289 may also contribute to bone size variation.