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Genetics of osteoporosis from genome-wide association studies: advances and challenges

Nature Reviews Genetics volume 13, pages 576–588 (2012)Cite this article

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A Corrigendum to this article was published on 07 August 2012

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Key Points

  • Osteoporosis is a common disease that is characterized by an increased propensity to fracture owing to decreased bone mass and bone quality. Clinically, osteoporosis is diagnosed when a patient presents with a fracture that has resulted from minimal trauma; however, osteoporosis is commonly diagnosed, for the purposes of preventive therapy, through measurement of bone mineral density (BMD).

  • Genome-wide association studies (GWASs) have been performed for BMD using various strategies, such as multi-ethnic studies, using extreme phenotypes and large-scale meta-analyses. Although the loci identified in these studies have been repeated between studies, the effect sizes are small, explaining the lack of amenability of the genetics of osteoporosis to genetic-linkage studies.

  • GWASs for fracture have also been carried out: fracture has a lower heritability than BMD and decreases with age. The findings from GWASs are in their preliminary stages, and the genetics of fracture risk is still poorly understood, although higher-powered studies and those targeting the most heritable age range of fractures will result in further understanding.

  • Highlighting proteins on shared pathways by GWASs for BMD and fracture have furthered insights into the pathophysiology of osteoporosis. Pathways highlighted include the WNT pathway, the RANK–RANKL–OPG pathway and genes that are involved in enochodral ossification.

  • Genes highlighted by GWASs include known drug targets for therapies effective for treatment of osteoporosis. Furthermore, the GWAS hits at present have little demonstrated use in predicting who will experience fractures.

  • Future highly powered GWASs will elucidate further variants that will be informative for osteoporosis physiology and treatment.

Abstract

Osteoporosis is among the most common and costly diseases and is increasing in prevalence owing to the ageing of our global population. Clinically defined largely through bone mineral density, osteoporosis and osteoporotic fractures have reasonably high heritabilities, prompting much effort to identify the genetic determinants of this disease. Genome-wide association studies have recently provided rapid insights into the allelic architecture of this condition, identifying 62 genome-wide-significant loci. Here, we review how these new loci provide an opportunity to explore how the genetics of osteoporosis can elucidate its pathophysiology, provide drug targets and allow for prediction of future fracture risk.

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Figure 1: Simplified depiction of members of the canonical WNT signalling pathway identified through genome-wide association studies for bone mineral density.
Figure 2: Simplified depictions of members of the RANK–RANKL–OPG signalling pathway identified through genome-wide association studies for bone mineral density.
Figure 3: Simplified depiction of members of the endochondral ossification pathway identified through genome-wide association studies for bone mineral density.

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Change history

  • 07 August 2012

    In table 2 of the above article, the P value for locus 7q31.31 should have been 7.3 × 10−9. Two citations to table 2 in the sections ‘GWASs for fracture’ and ‘Insights into pathophysiology’ were incorrectly cited as table 1. In the section ‘GWASs for fracture’, two reference citations were incorrectly cited as 32: they should have been 74 and 31, respectively. The blurb for reference 31 should have read 'Together with reference 32'. The authors and editors apologize for these errors.

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Acknowledgements

This work has been supported by the Canadian Institutes of Health Research, the Lady Davis Institute for Medical Research, Ministère de Développement économique, de l'Innovation et de l'Exportation du Québec, the Arthritis Research Campaign, the Wellcome Trust, Guy's & St. Thomas' NHS Foundation Trust and the King's College London Biomedical Centre. We would like to acknowledge the contributions of F. Rivadeneira, C. Greenwood and C. Polychronakos for their input on this Review.

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  1. Departments of Medicine, Human Genetics, Epidemiology and Biostatistics, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, H3T 1E2, Quebec, Canada

    J. Brent Richards & Hou-Feng Zheng

  2. Twin Research and Genetic Epidemiology, King's College London, London, UK

    J. Brent Richards & Tim D. Spector

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Glossary

deCODE genetics

An Icelandic company that specializes in the identification of genetic risk factors for disease.

Osteoporosis-pseudoglioma syndrome

An autosomal recessive disorder conferring juvenile osteoporosis and juvenile-onset blindness that is caused by mutations in lipoprotein-receptor-related protein 5 (LRP5).

Osteopetrosis

A syndrome of high bone mass caused by an imbalance in the constant remodelling of bone, which favours bone formation, or mutations leading to increased bone formation, such as activating mutations in low-density lipoprotein receptor-related protein 5 (LRP5).

Paget's disease

Focalized bone lesions characterized by enhanced bone remodelling and resultant overgrowth of bone, leading to an increased risk of fracture.

Cleidocranial dysplasia

An autosomal dominant condition characterized by defective differentiation of osteoblasts, resulting in impaired bone formation, short stature and abnormal teeth owing to mutations of runt-related transcription factor 2 (RUNX2), which encodes core-binding factor alpha 1.

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Richards, J., Zheng, HF. & Spector, T. Genetics of osteoporosis from genome-wide association studies: advances and challenges. Nat Rev Genet 13, 576–588 (2012). https://doi.org/10.1038/nrg3228

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