The Genetics of Bone Mass and Susceptibility to Bone Diseases

Overview

Journal Nat Rev Rheumatol

Specialty Rheumatology

Date 2016 Apr 8

PMID 27052486

Citations 33

Authors

David Karasik

Fernando Rivadeneira

Mark L Johnson

Affiliations

Soon will be listed here.

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.

Citing Articles

Unveiling two distinct osteolineage cell populations linked to age-related osteoporosis in adult mice through integrative single-cell analyses.

Zhou B, Huang H, Ding Z, Luo K, Chen Y, Han Y Cell Mol Life Sci. 2025; 82(1):106.

PMID: 40067455 PMC: 11896952. DOI: 10.1007/s00018-025-05597-w.

Healing sequelae following tooth extraction and dental implant placement in an aged, ovariectomy model.

Latimer J, Maekawa S, Shiba T, Fretwurst T, Chen M, Larsson L JBMR Plus. 2024; 8(10):ziae113.

PMID: 39347482 PMC: 11427826. DOI: 10.1093/jbmrpl/ziae113.

Copy Number Variation and Osteoporosis.

Lovsin N Curr Osteoporos Rep. 2023; 21(2):167-172.

PMID: 36795294 PMC: 10105686. DOI: 10.1007/s11914-023-00773-y.

Application of Single-Cell and Spatial Omics in Musculoskeletal Disorder Research.

Feng S, Li J, Tian J, Lu S, Zhao Y Int J Mol Sci. 2023; 24(3).

PMID: 36768592 PMC: 9917071. DOI: 10.3390/ijms24032271.

Vitamin D Receptor Gene Polymorphisms Affect Osteoporosis-Related Traits and Response to Antiresorptive Therapy.

Mondockova V, Kovacova V, Zemanova N, Babikova M, Martiniakova M, Galbavy D Genes (Basel). 2023; 14(1).

PMID: 36672934 PMC: 9858724. DOI: 10.3390/genes14010193.

References

Sims A, Shephard N, Carter K, Doan T, Dowling A, Duncan E . Genetic analyses in a sample of individuals with high or low BMD shows association with multiple Wnt pathway genes. J Bone Miner Res. 2007; 23(4):499-506. DOI: 10.1359/jbmr.071113. View

Deng F, Xiao P, Lei S, Zhang L, Yang F, Tang Z . Bivariate whole genome linkage analysis for femoral neck geometric parameters and total body lean mass. J Bone Miner Res. 2007; 22(6):808-16. DOI: 10.1359/jbmr.070303. View

Burgers T, Williams B . Regulation of Wnt/β-catenin signaling within and from osteocytes. Bone. 2013; 54(2):244-9. PMC: 3652284. DOI: 10.1016/j.bone.2013.02.022. View

Zheng H, Duncan E, Yerges-Armstrong L, Eriksson J, Bergstrom U, Leo P . Meta-analysis of genome-wide studies identifies MEF2C SNPs associated with bone mineral density at forearm. J Med Genet. 2013; 50(7):473-8. PMC: 3769185. DOI: 10.1136/jmedgenet-2012-101287. View

Kryukov G, Shpunt A, Stamatoyannopoulos J, Sunyaev S . Power of deep, all-exon resequencing for discovery of human trait genes. Proc Natl Acad Sci U S A. 2009; 106(10):3871-6. PMC: 2656172. DOI: 10.1073/pnas.0812824106. View

de Vrieze E, Zethof J, Schulte-Merker S, Flik G, Metz J . Identification of novel osteogenic compounds by an ex-vivo sp7:luciferase zebrafish scale assay. Bone. 2015; 74:106-13. DOI: 10.1016/j.bone.2015.01.006. View

Nikolskiy I, Conrad D, Chun S, Fay J, Cheverud J, Lawson H . Using whole-genome sequences of the LG/J and SM/J inbred mouse strains to prioritize quantitative trait genes and nucleotides. BMC Genomics. 2015; 16:415. PMC: 4445795. DOI: 10.1186/s12864-015-1592-3. View

Kernstock S, Davydova E, Jakobsson M, Moen A, Pettersen S, Maelandsmo G . Lysine methylation of VCP by a member of a novel human protein methyltransferase family. Nat Commun. 2012; 3:1038. DOI: 10.1038/ncomms2041. View

Vannahme C, Smyth N, Miosge N, Gosling S, Frie C, Paulsson M . Characterization of SMOC-1, a novel modular calcium-binding protein in basement membranes. J Biol Chem. 2002; 277(41):37977-86. DOI: 10.1074/jbc.M203830200. View

10.

Brunkow M, Gardner J, Van Ness J, Paeper B, Kovacevich B, Proll S . Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Am J Hum Genet. 2001; 68(3):577-89. PMC: 1274471. DOI: 10.1086/318811. View

11.

Paternoster L, Lorentzon M, Lehtimaki T, Eriksson J, Kahonen M, Raitakari O . Genetic determinants of trabecular and cortical volumetric bone mineral densities and bone microstructure. PLoS Genet. 2013; 9(2):e1003247. PMC: 3578773. DOI: 10.1371/journal.pgen.1003247. View

12.

Wang Y, Liu A, Mills J, Boehnke M, Wilson A, Bailey-Wilson J . Pleiotropy analysis of quantitative traits at gene level by multivariate functional linear models. Genet Epidemiol. 2015; 39(4):259-75. PMC: 4443751. DOI: 10.1002/gepi.21895. View

13.

Pedersen B, Febbraio M . Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat Rev Endocrinol. 2012; 8(8):457-65. DOI: 10.1038/nrendo.2012.49. View

14.

Gong Y, Slee R, Fukai N, Rawadi G, Roman-Roman S, Reginato A . LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell. 2001; 107(4):513-23. DOI: 10.1016/s0092-8674(01)00571-2. View

15.

Komori T, Yagi H, Nomura S, Yamaguchi A, Sasaki K, Deguchi K . Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell. 1997; 89(5):755-64. DOI: 10.1016/s0092-8674(00)80258-5. View

16.

Masi L, Agnusdei D, Bilezikian J, Chappard D, Chapurlat R, Cianferotti L . Taxonomy of rare genetic metabolic bone disorders. Osteoporos Int. 2015; 26(10):2529-58. DOI: 10.1007/s00198-015-3188-9. View

17.

Kung A, Xiao S, Cherny S, Li G, Gao Y, Tso G . Association of JAG1 with bone mineral density and osteoporotic fractures: a genome-wide association study and follow-up replication studies. Am J Hum Genet. 2010; 86(2):229-39. PMC: 2820171. DOI: 10.1016/j.ajhg.2009.12.014. View

18.

Cheung C, Chan V, Kung A . A differential association of ALOX15 polymorphisms with bone mineral density in pre- and post-menopausal women. Hum Hered. 2007; 65(1):1-8. DOI: 10.1159/000106057. View

19.

Staehling-Hampton K, Proll S, Paeper B, Zhao L, Charmley P, Brown A . A 52-kb deletion in the SOST-MEOX1 intergenic region on 17q12-q21 is associated with van Buchem disease in the Dutch population. Am J Med Genet. 2002; 110(2):144-52. DOI: 10.1002/ajmg.10401. View

20.

Xiao S, Kung A, Gao Y, Lau K, Ma A, Zhang Z . Post-genome wide association studies and functional analyses identify association of MPP7 gene variants with site-specific bone mineral density. Hum Mol Genet. 2011; 21(7):1648-57. DOI: 10.1093/hmg/ddr586. View