Phenotypic Dissection of Bone Mineral Density Reveals Skeletal Site Specificity and Facilitates the Identification of Novel Loci in the Genetic Regulation of Bone Mass Attainment

Abstract

Heritability of bone mineral density (BMD) varies across skeletal sites, reflecting different relative contributions of genetic and environmental influences. To quantify the degree to which common genetic variants tag and environmental factors influence BMD, at different sites, we estimated the genetic (rg) and residual (re) correlations between BMD measured at the upper limbs (UL-BMD), lower limbs (LL-BMD) and skull (SK-BMD), using total-body DXA scans of ∼4,890 participants recruited by the Avon Longitudinal Study of Parents and their Children (ALSPAC). Point estimates of rg indicated that appendicular sites have a greater proportion of shared genetic architecture (LL-/UL-BMD rg = 0.78) between them, than with the skull (UL-/SK-BMD rg = 0.58 and LL-/SK-BMD rg = 0.43). Likewise, the residual correlation between BMD at appendicular sites (re = 0.55) was higher than the residual correlation between SK-BMD and BMD at appendicular sites (re = 0.20–0.24). To explore the basis for the observed differences in rg and re, genome-wide association meta-analyses were performed (n∼9,395), combining data from ALSPAC and the Generation R Study identifying 15 independent signals from 13 loci associated at genome-wide significant level across different skeletal regions. Results suggested that previously identified BMD-associated variants may exert site-specific effects (i.e. differ in the strength of their association and magnitude of effect across different skeletal sites). In particular, variants at CPED1 exerted a larger influence on SK-BMD and UL-BMD when compared to LL-BMD (P = 2.01×10−37), whilst variants at WNT16 influenced UL-BMD to a greater degree when compared to SK- and LL-BMD (P = 2.31×10−14). In addition, we report a novel association between RIN3 (previously associated with Paget's disease) and LL-BMD (rs754388: β = 0.13, SE = 0.02, P = 1.4×10−10). Our results suggest that BMD at different skeletal sites is under a mixture of shared and specific genetic and environmental influences. Allowing for these differences by performing genome-wide association at different skeletal sites may help uncover new genetic influences on BMD.

Osteocyte-specific WNT1 regulates osteoblast function during bone homeostasis

“…The rescued bone phenotypes of Wnt1 sw/sw mice strongly suggest that other WNT ligands, including excellent candidates such as WNT16, WNT10b, and WNT7b, can compensate for loss of Wnt1 in Wnt1 sw/sw mice (10)(11)(12)(13)(14)(15)(16)(17). Despite the potential redundancy of multiple WNT ligands that affect bone formation, the incomplete restoration of bone volume by Scl-Ab treatment in Wnt1 sw/sw mice suggests that WNT1 clearly has a critical function in bone homeostasis.…”

“…Genetic studies of LRP5 in human and mouse strongly suggest that canonical Wnt signaling regulates postnatal bone formation (2)(3)(4)(5). Further genetic studies with β-catenin and other Wnt ligands using various mouse models provided additional evidence that corroborate the critical function of Wnt signaling in skeletal development and bone homeostasis (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Several recent studies also reported that Wnt signaling directly regulates osteoclast function (18)(19)(20)(21)(22).…”

Differential Recognition Preferences of the Three Src Homology 3 (SH3) Domains from the Adaptor CD2-associated Protein (CD2AP) and Direct Association with Ras and Rab Interactor 3 (RIN3)

“…Furthermore, most recently, RIN3 has been linked to modulation of bone mineral density of the lower limbs (56). CD2AP has also been associated with the bone disorder Kashin-Beck disease (57).…”

Quantitative imaging methods in osteoporosis

“…It is believed that there are skeletal-site specific effects for fracture risk including different roles for cortical versus trabecular bone, justifying efforts to separately analyze these entities (55). Quantitative computed tomography (QCT) yields volumetric 3D measurements by utilizing low dose scan protocols on a standard CT scanner or by performing high resolution-peripheral quantitative computed tomography (HR-)pQCT with the use of a dedicated extremity scanner (56).…”