Hebrew SeniorLife Institute for Aging Research, 1200 Centre Street, Boston, Massachusetts 02131, USA.
J Clin Endocrinol Metab. 2012 Oct;97(10):E1958-77. doi: 10.1210/jc.2012-1890. Epub 2012 Sep 10.
The primary goals of genome-wide association studies (GWAS) are to discover new molecular and biological pathways involved in the regulation of bone metabolism that can be leveraged for drug development. In addition, the identified genetic determinants may be used to enhance current risk factor profiles.
There have been more than 40 published GWAS on skeletal phenotypes, predominantly focused on dual-energy x-ray absorptiometry-derived bone mineral density (BMD) of the hip and spine.
Sixty-six BMD loci have been replicated across all the published GWAS, confirming the highly polygenic nature of BMD variation. Only seven of the 66 previously reported genes (LRP5, SOST, ESR1, TNFRSF11B, TNFRSF11A, TNFSF11, PTH) from candidate gene association studies have been confirmed by GWAS. Among 59 novel BMD GWAS loci that have not been reported by previous candidate gene association studies, some have been shown to be involved in key biological pathways involving the skeleton, particularly Wnt signaling (AXIN1, LRP5, CTNNB1, DKK1, FOXC2, HOXC6, LRP4, MEF2C, PTHLH, RSPO3, SFRP4, TGFBR3, WLS, WNT3, WNT4, WNT5B, WNT16), bone development: ossification (CLCN7, CSF1, MEF2C, MEPE, PKDCC, PTHLH, RUNX2, SOX6, SOX9, SPP1, SP7), mesenchymal-stem-cell differentiation (FAM3C, MEF2C, RUNX2, SOX4, SOX9, SP7), osteoclast differentiation (JAG1, RUNX2), and TGF-signaling (FOXL1, SPTBN1, TGFBR3). There are still 30 BMD GWAS loci without prior molecular or biological evidence of their involvement in skeletal phenotypes. Other skeletal phenotypes that either have been or are being studied include hip geometry, bone ultrasound, quantitative computed tomography, high-resolution peripheral quantitative computed tomography, biochemical markers, and fractures such as vertebral, nonvertebral, hip, and forearm.
Although several challenges lie ahead as GWAS moves into the next generation, there are prospects of new discoveries in skeletal biology. This review integrates findings from previous GWAS and provides a roadmap for future directions building on current GWAS successes.
全基因组关联研究（GWAS）的主要目标是发现新的分子和生物学途径，这些途径参与调节骨代谢，可以用于药物开发。此外，鉴定出的遗传决定因素可用于增强当前的危险因素概况。
已经有 40 多项关于骨骼表型的 GWAS 发表，主要集中在双能 X 射线吸收仪（DXA）测定的髋部和脊柱骨矿物质密度（BMD）上。
在所有已发表的 GWAS 中，已经复制了 66 个 BMD 位点，证实了 BMD 变异的高度多基因性质。在候选基因关联研究中，只有 7 个先前报道的基因（LRP5、SOST、ESR1、TNFRSF11B、TNFRSF11A、TNFSF11、PTH）得到了 GWAS 的证实。在 59 个未被先前候选基因关联研究所报道的新的 BMD GWAS 位点中，一些已被证明参与了涉及骨骼的关键生物学途径，特别是 Wnt 信号（AXIN1、LRP5、CTNNB1、DKK1、FOXC2、HOXC6、LRP4、MEF2C、PTHLH、RSPO3、SFRP4、TGFBR3、WLS、WNT3、WNT4、WNT5B、WNT16）、骨发育：骨化（CLCN7、CSF1、MEF2C、MEPE、PKDCC、PTHLH、RUNX2、SOX6、SOX9、SPP1、SP7）、间充质干细胞分化（FAM3C、MEF2C、RUNX2、SOX4、SOX9、SP7）、破骨细胞分化（JAG1、RUNX2）和 TGF 信号（FOXL1、SPTBN1、TGFBR3）。仍然有 30 个 BMD GWAS 位点没有分子或生物学证据表明它们参与骨骼表型。其他骨骼表型，无论是已经研究过的还是正在研究的，包括髋部几何形状、骨超声、定量计算机断层扫描、高分辨率外周定量计算机断层扫描、生化标志物以及椎体、非椎体、髋部和前臂骨折等。
尽管 GWAS 进入下一代还面临一些挑战，但骨骼生物学仍有新发现的前景。本综述整合了先前 GWAS 的研究结果，并为基于当前 GWAS 成功的未来方向提供了路线图。
