Key Points
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The genetics of osteoporosis is a rapidly evolving field, which has been greatly expanded by increased understanding of the human genome
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The list of identified loci associated with osteoporosis phenotypes is growing rapidly, and still incomplete
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Studies of monogenic bone diseases and genome-wide association studies of complex traits have identified dozens of genes and loci that influence skeletal traits
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Further knowledge of the genetics of osteoporosis will emerge from mining large databases containing a wealth of genomic information
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Many candidate osteoporosis-related loci require detailed functional follow-up to understand the underlying biological mechanisms determining trait variation
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Despite this wealth of new genetic information, its application to the clinical management of osteoporosis remains in its infancy
Abstract
Osteoporosis is characterized by low bone mass and an increased risk of fracture. Genetic factors, environmental factors and gene–environment interactions all contribute to a person's lifetime risk of developing an osteoporotic fracture. This Review summarizes key advances in understanding of the genetics of bone traits and their role in osteoporosis. Candidate-gene approaches dominated this field 20 years ago, but clinical and preclinical genetic studies published in the past 5 years generally utilize more-sophisticated and better-powered genome-wide association studies (GWAS). High-throughput DNA sequencing, large genomic databases and improved methods of data analysis have greatly accelerated the gene-discovery process. Linkage analyses of single-gene traits that segregate in families with extreme phenotypes have led to the elucidation of critical pathways controlling bone mass. For example, components of the Wnt–β-catenin signalling pathway have been validated (in both GWAS and functional studies) as contributing to various bone phenotypes. These notable advances in gene discovery suggest that the next decade will witness cataloguing of the hundreds of genes that influence bone mass and osteoporosis, which in turn will provide a roadmap for the development of new drugs that target diseases of low bone mass, including osteoporosis.
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Change history
22 July 2016
In Table 1 of this Review, the protein names and protein functions for TNFSF11 and TNFRSF11A were incorrectly associated. The entries have been corrected and the protein function for TNFRSF11A has been clarified in the online version of the article. The authors apologize for this error.
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Acknowledgements
F.R.'s research is supported by a grant from the Netherlands Organization for Scientific Research (NWO-ZonMw VIDI 016.136.367). D.K. is supported by ERC FP7-PEOPLE-2012-Marie Curie Career Integration Grants and Israel Science Foundation (No. 1283/14). M.L.J.'s work is supported by a grant from the NIH (NIA P01 AG039355). The original artwork for the skeleton drawing in Fig. 2 is from a collection of anatomical drawings by the late Cecil G. Johnson (1920–2004), uncle of M.L.J.
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Osteoporosis-related loci discovered by GWAS, for BMD, bone ultrasound, and fracture, with the nearest candidate genes. (PDF 311 kb)
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Karasik, D., Rivadeneira, F. & Johnson, M. The genetics of bone mass and susceptibility to bone diseases. Nat Rev Rheumatol 12, 323–334 (2016). https://doi.org/10.1038/nrrheum.2016.48
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DOI: https://doi.org/10.1038/nrrheum.2016.48
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