Genetics of Osteoporosis from Genome-wide Association Studies: Advances and Challenges

Overview

Journal Nat Rev Genet

Specialty Genetics

Date 2012 Jul 19

PMID 22805710

Citations 169

Authors

J Brent Richards

Hou-Feng Zheng

Tim D Spector

Affiliations

Soon will be listed here.

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.

Citing Articles

The mediating role of thyroid-related hormones between thyroid dysfunction diseases and osteoporosis: a mediation mendelian randomization study.

Liu R, Fan W, Hu J, Xu K, Huang Z, Liu Y Sci Rep. 2025; 15(1):4121.

PMID: 39901040 PMC: 11791035. DOI: 10.1038/s41598-025-88412-7.

The rs1800012 polymorphism is associated with osteoporosis or fracture risk: a meta-analysis of 30 studies.

Xu P, Wang Y, Wu X, Wang W, Wang Q, Lin W Int J Burns Trauma. 2025; 14(6):148-159.

PMID: 39850783 PMC: 11751553. DOI: 10.62347/KKAM3344.

Crispant analysis in zebrafish as a tool for rapid functional screening of disease-causing genes for bone fragility.

Debaenst S, Jarayseh T, De Saffel H, Bek J, Boone M, Josipovic I Elife. 2025; 13.

PMID: 39817421 PMC: 11737869. DOI: 10.7554/eLife.100060.

Selective Pyk2 inhibition enhances bone restoration through SCARA5-mediated bone marrow remodeling in ovariectomized mice.

Liu Y, Nishiura M, Fujii M, Sandhu S, Yawaka Y, Yamazaki Y Cell Commun Signal. 2024; 22(1):561.

PMID: 39578816 PMC: 11583405. DOI: 10.1186/s12964-024-01945-8.

Wnt/β-catenin signaling pathway as an important mediator in muscle and bone crosstalk: A systematic review.

Lin W, Chow S, Cui C, Liu C, Wang Q, Chai S J Orthop Translat. 2024; 47:63-73.

PMID: 39007034 PMC: 11245956. DOI: 10.1016/j.jot.2024.06.003.

References

Smits P, Dy P, Mitra S, Lefebvre V . Sox5 and Sox6 are needed to develop and maintain source, columnar, and hypertrophic chondrocytes in the cartilage growth plate. J Cell Biol. 2004; 164(5):747-58. PMC: 2172159. DOI: 10.1083/jcb.200312045. View

Duncan E, Danoy P, Kemp J, Leo P, McCloskey E, Nicholson G . Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk. PLoS Genet. 2011; 7(4):e1001372. PMC: 3080863. DOI: 10.1371/journal.pgen.1001372. View

Andrew T, Antioniades L, Scurrah K, MacGregor A, Spector T . Risk of wrist fracture in women is heritable and is influenced by genes that are largely independent of those influencing BMD. J Bone Miner Res. 2004; 20(1):67-74. DOI: 10.1359/JBMR.041015. View

Duncan E, Brown M . Clinical review 2: Genetic determinants of bone density and fracture risk--state of the art and future directions. J Clin Endocrinol Metab. 2010; 95(6):2576-87. DOI: 10.1210/jc.2009-2406. View

McClellan J, King M . Genetic heterogeneity in human disease. Cell. 2010; 141(2):210-7. DOI: 10.1016/j.cell.2010.03.032. View

Suhre K, Shin S, Petersen A, Mohney R, Meredith D, Wagele B . Human metabolic individuality in biomedical and pharmaceutical research. Nature. 2011; 477(7362):54-60. PMC: 3832838. DOI: 10.1038/nature10354. View

Lewiecki E . Sclerostin: a novel target for intervention in the treatment of osteoporosis. Discov Med. 2011; 12(65):263-73. View

Estrada K, Styrkarsdottir U, Evangelou E, Hsu Y, Duncan E, Ntzani E . Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nat Genet. 2012; 44(5):491-501. PMC: 3338864. DOI: 10.1038/ng.2249. View

Rivadeneira F, Styrkarsdottir U, Estrada K, Halldorsson B, Hsu Y, Richards J . Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies. Nat Genet. 2009; 41(11):1199-206. PMC: 2783489. DOI: 10.1038/ng.446. View

10.

Neer R, Arnaud C, Zanchetta J, Prince R, Gaich G, Reginster J . Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med. 2001; 344(19):1434-41. DOI: 10.1056/NEJM200105103441904. View

11.

Ettinger B, Black D, Mitlak B, Knickerbocker R, Nickelsen T, Genant H . Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA. 1999; 282(7):637-45. DOI: 10.1001/jama.282.7.637. View

12.

Simonet W, Lacey D, Dunstan C, Kelley M, Chang M, Luthy R . Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell. 1997; 89(2):309-19. DOI: 10.1016/s0092-8674(00)80209-3. View

13.

Guo J, Liu M, Yang D, Bouxsein M, Saito H, Galvin R . Suppression of Wnt signaling by Dkk1 attenuates PTH-mediated stromal cell response and new bone formation. Cell Metab. 2010; 11(2):161-71. PMC: 2819982. DOI: 10.1016/j.cmet.2009.12.007. View

14.

Xiong J, Onal M, Jilka R, Weinstein R, Manolagas S, OBrien C . Matrix-embedded cells control osteoclast formation. Nat Med. 2011; 17(10):1235-41. PMC: 3192296. DOI: 10.1038/nm.2448. View

15.

Guerrini M, Sobacchi C, Cassani B, Abinun M, Kilic S, Pangrazio A . Human osteoclast-poor osteopetrosis with hypogammaglobulinemia due to TNFRSF11A (RANK) mutations. Am J Hum Genet. 2008; 83(1):64-76. PMC: 2443850. DOI: 10.1016/j.ajhg.2008.06.015. View

16.

Gauthier J, Chauret N, Cromlish W, Desmarais S, Duong L, Falgueyret J . The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. Bioorg Med Chem Lett. 2008; 18(3):923-8. DOI: 10.1016/j.bmcl.2007.12.047. View

17.

Peacock M, Koller D, Lai D, Hui S, Foroud T, Econs M . Bone mineral density variation in men is influenced by sex-specific and non sex-specific quantitative trait loci. Bone. 2009; 45(3):443-8. PMC: 2725190. DOI: 10.1016/j.bone.2009.05.002. View

18.

Li L, Krantz I, Deng Y, Genin A, Banta A, Collins C . Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet. 1997; 16(3):243-51. DOI: 10.1038/ng0797-243. View

19.

Van Wesenbeeck L, Cleiren E, Gram J, Beals R, Benichou O, Scopelliti D . Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density. Am J Hum Genet. 2003; 72(3):763-71. PMC: 1180253. DOI: 10.1086/368277. View

20.

Engin F, Yao Z, Yang T, Zhou G, Bertin T, Ming Jiang M . Dimorphic effects of Notch signaling in bone homeostasis. Nat Med. 2008; 14(3):299-305. PMC: 2671578. DOI: 10.1038/nm1712. View