Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Genome-wide association study identifies variants at CSF1, OPTN and TNFRSF11A as genetic risk factors for Paget's disease of bone

This article has been updated


Paget's disease of bone (PDB) is a common disorder with a strong genetic component characterized by focal increases in bone turnover, which in some cases is caused by mutations in SQSTM1. To identify additional susceptibility genes, we performed a genome-wide association study in 750 individuals with PDB (cases) without SQSTM1 mutations and 1,002 controls and identified three candidate disease loci, which were then replicated in an independent set of 500 cases and 535 controls. The strongest signal was with rs484959 on 1p13 near the CSF1 gene (P = 5.38 × 10−24). Significant associations were also observed with rs1561570 on 10p13 within the OPTN gene (P = 6.09 × 10−13) and with rs3018362 on 18q21 near the TNFRSF11A gene (P = 5.27 × 10−13). These studies provide new insights into the pathogenesis of PDB and identify OPTN, CSF1 and TNFRSF11A as candidate genes for disease susceptibility.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Detection of loci conferring susceptibility to PDB by genome-wide association.
Figure 2: Details of loci associated with PDB.

Change history

  • 16 May 2010

    In the version of this paper originally published online, the name of the 12th author was misspelled (the correct spelling is Javier del Pino Montes), affiliation 10 was incorrect (the correct affiliation is “Unidad de Medicina Molecular, Departamento de Medicina, Universidad de Salamanca and Hospital Universitario de Salamanca, RETICEF, Salamanca, Spain”) and the following sentence was missing from the Acknowledgments ( “The work was also supported by grants from Cancer Research UK (C348/A3758, C348/A8896), and the Medical Research Council (G0000657-53203) to M.G.D. and A.T.”). These errors have been corrected for the print, PDF and HTML versions of this article.


  1. 1

    Cooper, C. et al. The epidemiology of Paget's disease in Britain: is the prevalence decreasing? J. Bone Miner. Res. 14, 192–197 (1999).

    Google Scholar 

  2. 2

    Siris, E.S. Paget's disease of bone. J. Bone Miner. Res. 13, 1061–1065 (1998).

    Google Scholar 

  3. 3

    Morales-Piga, A.A., Rey-Rey, J.S., Corres-Gonzalez, J., Garcia-Sagredo, J.M. & Lopez-Abente, G. Frequency and characteristics of familial aggregation of Paget's disease of bone. J. Bone Miner. Res. 10, 663–670 (1995).

    Google Scholar 

  4. 4

    Laurin, N., Brown, J.P., Morissette, J. & Raymond, V. Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in Paget disease of bone. Am. J. Hum. Genet. 70, 1582–1588 (2002).

    Google Scholar 

  5. 5

    Hocking, L.J. et al. Domain-specific mutations in sequestosome 1 (SQSTM1) cause familial and sporadic Paget's disease. Hum. Mol. Genet. 11, 2735–2739 (2002).

    Google Scholar 

  6. 6

    Lucas, G.J. et al. Identification of a major locus for Paget's disease on chromosome 10p13 in families of British descent. J. Bone Miner. Res. 23, 58–63 (2008).

    Google Scholar 

  7. 7

    Hocking, L.J. et al. Genomewide search in familial Paget disease of bone shows evidence of genetic heterogeneity with candidate loci on chromosomes 2q36, 10p13, and 5q35. Am. J. Hum. Genet. 69, 1055–1061 (2001).

    Google Scholar 

  8. 8

    Laurin, N. et al. Paget disease of bone: mapping of two loci at 5q35-qter and 5q31. Am. J. Hum. Genet. 69, 528–543 (2001).

    Google Scholar 

  9. 9

    Tenesa, A. et al. Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21. Nat. Genet. 40, 631–637 (2008).

    Google Scholar 

  10. 10

    Clayton, D.G. et al. Population structure, differential bias and genomic control in a large-scale, case-control association study. Nat. Genet. 37, 1243–1246 (2005).

    Google Scholar 

  11. 11

    Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).

  12. 12

    Novembre, J. et al. Genes mirror geography within Europe. Nature 456, 98–101 (2008).

    Google Scholar 

  13. 13

    Tsurukai, T., Udagawa, N., Matsuzaki, K., Takahashi, N. & Suda, T. Roles of macrophage-colony stimulating factor and osteoclast differentiation factor in osteoclastogenesis. J. Bone Miner. Metab. 18, 177–184 (2000).

    Google Scholar 

  14. 14

    Bouyer, P. et al. Colony-stimulating factor-1 increases osteoclast intracellular pH and promotes survival via the electroneutral Na/HCO3 cotransporter NBCn1. Endocrinology 148, 831–840 (2007).

    Google Scholar 

  15. 15

    Van Wesenbeeck, L. et al. The osteopetrotic mutation toothless (tl) is a loss-of-function frameshift mutation in the rat Csf1 gene: evidence of a crucial role for CSF-1 in osteoclastogenesis and endochondral ossification. Proc. Natl. Acad. Sci. USA 99, 14303–14308 (2002).

    Google Scholar 

  16. 16

    Wiktor-Jedrzejczak, W. et al. Total absence of colony-stimulating factor 1 in the macrophage-deficient osteopetrotic (op/op) mouse. Proc. Natl. Acad. Sci. USA 87, 4828–4832 (1990).

    Google Scholar 

  17. 17

    Neale, S.D., Schulze, E., Smith, R. & Athanasou, N.A. The influence of serum cytokines and growth factors on osteoclast formation in Paget's disease. QJM 95, 233–240 (2002).

    Google Scholar 

  18. 18

    van Es, M.A. et al. Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis. Nat. Genet. 41, 1083–1087 (2009).

    Google Scholar 

  19. 19

    Rioux, J.D. et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat. Genet. 39, 596–604 (2007).

    Google Scholar 

  20. 20

    Rezaie, T. et al. Adult-onset primary open-angle glaucoma caused by mutations in optineurin. Science 295, 1077–1079 (2002).

    Google Scholar 

  21. 21

    Rezaie, T., Waitzman, D.M., Seeman, J.L., Kaufman, P.L. & Sarfarazi, M. Molecular cloning and expression profiling of optineurin in the rhesus monkey. Invest. Ophthalmol. Vis. Sci. 46, 2404–2410 (2005).

    Google Scholar 

  22. 22

    Zhu, G., Wu, C.J., Zhao, Y. & Ashwell, J.D. Optineurin negatively regulates TNFα-induced NF-κB activation by competing with NEMO for ubiquitinated RIP. Curr. Biol. 17, 1438–1443 (2007).

    Google Scholar 

  23. 23

    Sudhakar, C., Nagabhushana, A., Jain, N. & Swarup, G. NF-κB mediates tumor necrosis factor α-induced expression of optineurin, a negative regulator of NF-κB. PLoS One 4, e5114 (2009).

    Google Scholar 

  24. 24

    Sahlender, D.A. et al. Optineurin links myosin VI to the Golgi complex and is involved in Golgi organization and exocytosis. J. Cell Biol. 169, 285–295 (2005).

    Google Scholar 

  25. 25

    Watts, G.D. et al. Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat. Genet. 36, 377–381 (2004).

    Google Scholar 

  26. 26

    Li, J. et al. RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism. Proc. Natl. Acad. Sci. USA 97, 1566–1571 (2000).

    Google Scholar 

  27. 27

    Villa, A., Guerrini, M.M., Cassani, B., Pangrazio, A. & Sobacchi, C. Infantile malignant, autosomal recessive osteopetrosis: the rich and the poor. Calcif. Tissue Int. 84, 1–12 (2009).

    Google Scholar 

  28. 28

    Hughes, A.E. et al. Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis. Nat. Genet. 24, 45–48 (2000).

    Google Scholar 

  29. 29

    Nakatsuka, K., Nishizawa, Y. & Ralston, S.H. Phenotypic characterization of early onset Paget's disease of bone caused by a 27-bp duplication in the TNFRSF11A gene. J. Bone Miner. Res. 18, 1381–1385 (2003).

    Google Scholar 

  30. 30

    Whyte, M.P. & Hughes, A.E. Expansile skeletal hyperphosphatasia is caused by a 15-base pair tandem duplication in TNFRSF11A encoding RANK and is allelic to familial expansile osteolysis. J. Bone Miner. Res. 17, 26–29 (2002).

    Google Scholar 

  31. 31

    Wuyts, W. et al. Evaluation of the role of RANK and OPG genes in Paget's disease of bone. Bone 28, 104–107 (2001).

    Google Scholar 

  32. 32

    Hocking, L. et al. Familial Paget's disease of bone: patterns of inheritance and frequency of linkage to chromosome 18q. Bone 26, 577–580 (2000).

    Google Scholar 

  33. 33

    Styrkarsdottir, U. et al. Multiple genetic loci for bone mineral density and fractures. N. Engl. J. Med. 358, 2355–2365 (2008).

    Google Scholar 

  34. 34

    Rivadeneira, F. et al. Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies. Nat. Genet. 41, 1199–1206 (2009).

    Google Scholar 

  35. 35

    Styrkarsdottir, U. et al. New sequence variants associated with bone mineral density. Nat. Genet. 41, 15–17 (2009).

    Google Scholar 

  36. 36

    Saito, K. et al. A novel binding protein composed of homophilic tetramer exhibits unique properties for the small GTPase Rab5. J. Biol. Chem. 277, 3412–3418 (2002).

    Google Scholar 

  37. 37

    Barrett, J.C., Fry, B., Maller, J. & Daly, M.J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).

    Google Scholar 

  38. 38

    Langston, A.L. et al. Randomized trial of intensive bisphosphonate treatment versus symptomatic management in Paget's disease of bone. J. Bone Miner. Res. 25, 20–31 (2010).

    Google Scholar 

  39. 39

    Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

    Google Scholar 

  40. 40

    Price, A.L. et al. Long-range LD can confound genome scans in admixed populations. Am. J. Hum. Genet. 83, 132–135 (2008).

    Google Scholar 

  41. 41

    Li, Y. & Abecasis, G.R. Mach 1.0: Rapid haplotype reconstruction and missing genotype inference. Am. J. Hum. Genet. S79, 2290 (2006).

    Google Scholar 

  42. 42

    Li, Y., Willer, C., Sanna, S. & Abecasis, G. Genotype imputation. Annu. Rev. Genomics Hum. Genet. 10, 387–406 (2009).

    Google Scholar 

  43. 43

    Pe'er, I., Yelensky, R., Altshuler, D. & Daly, M.J. Estimation of the multiple testing burden for genomewide association studies of nearly all common variants. Genet. Epidemiol. 32, 381–385 (2008).

    Google Scholar 

Download references


We acknowledge the contribution of the many participants who provided samples for the analysis. We thank L. Murphy and A. Fawkes of the Wellcome Trust Clinical Research Facility for technical support with the Illumina genotyping. We also thank A. Khatib for assistance with data management. The study was supported in part by grants to S.H.R. from the Arthritis Research Campaign (grants 13724, 17646 and 15389) and a grant to O.M.E.A. and S.H.R. from the National Association for Relief of Paget's Disease. The work was also supported by grants from Cancer Research UK (C348/A3758, C348/A8896), and the Medical Research Council (G0000657-53203) to M.G.D. and A.T.

Author information




O.M.E.A. contributed to study design, oversaw the genotyping, performed data management, quality control, statistical and bioinformatic analyses and wrote the first draft of the manuscript. S.H.R. designed the study, obtained funding, coordinated the sample collection and phenotyping and revised the manuscript. A.L.L., T.C., R.D., W.D.F., M.J.H., G.I., G.C.N., J.d.P.M., R.G.-S., M.d.S. and J.P.W. contributed toward clinical sample collection and phenotyping. M.G.D. and A.T. provided genotype data for the stage 1 control samples. M.R.V. and N.A. assisted in sample preparation and performed DNA sequencing to identify samples with SQSTM1 mutations. All authors critically reviewed the article for important intellectual content and approved the final manuscript.

Corresponding author

Correspondence to Stuart H Ralston.

Ethics declarations

Competing interests

S.H.R. and O.M.E.A. have submitted patents on the use of various genetic markers as diagnostic tests in PDB, including those described in this paper.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–3 and Supplementary Tables 1–8 (PDF 252 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Albagha, O., Visconti, M., Alonso, N. et al. Genome-wide association study identifies variants at CSF1, OPTN and TNFRSF11A as genetic risk factors for Paget's disease of bone. Nat Genet 42, 520–524 (2010).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing