Genome-Wide Association Studies of Skeletal Phenotypes: What We Have Learned and Where We Are Headed

Context: 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. Evidence Acquisition: 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. Evidence Synthesis: 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. Conclusions: 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. (J Clin Endocrinol Metab 97: E1958-E1977, 2012)