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

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.

骨骼不同部位的骨密度（BMD）遗传力存在差异，这反映了遗传与环境影响的相对贡献各不相同。为量化常见遗传变异标记及环境因素对不同部位骨密度的影响程度，我们利用雅芳亲子纵向研究（ALSPAC）招募的约4890名参与者的全身双能X线吸收法（DXA）扫描数据，估算了上肢骨密度（UL-BMD）、下肢骨密度（LL-BMD）与颅骨骨密度（SK-BMD）之间的遗传相关系数（rg）及残差相关系数（re）。遗传相关系数的点估计结果显示，与颅骨相比，四肢骨骼部位间共享的遗传架构比例更高：下肢/上肢骨密度rg=0.78，上肢/颅骨骨密度rg=0.58，下肢/颅骨骨密度rg=0.43。同理，四肢骨骼部位骨密度的残差相关系数（re=0.55）也高于颅骨与四肢骨骼部位骨密度间的残差相关系数（re=0.20–0.24）。为探究上述遗传及残差相关系数差异的成因，我们结合ALSPAC与Generation R研究的数据开展了全基因组关联荟萃分析（样本量约9395），从13个基因座中鉴定出15个独立关联信号，这些信号在不同骨骼区域均达到全基因组显著性水平。研究结果提示，此前已发现的骨密度相关变异可能存在部位特异性效应（即不同骨骼部位的关联强度及效应大小存在差异）。具体而言，CPED1基因座的变异对颅骨及上肢骨密度的影响较下肢骨密度更为显著（P=2.01×10^-37）；而WNT16基因座的变异对上肢骨密度的影响则强于颅骨及下肢骨密度（P=2.31×10^-14）。此外，我们还报道了RIN3（此前被发现与佩吉特骨病相关）与下肢骨密度间的新关联（rs754388：β=0.13，SE=0.02，P=1.4×10^-10）。我们的研究结果表明，不同骨骼部位的骨密度同时受到共享及特异性的遗传与环境影响。针对不同骨骼部位开展全基因组关联研究，充分考虑这些差异，将有助于揭示骨密度的新遗传影响因素。