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

Omar M E Albagha; Micaela R Visconti; Nerea Alonso; Anne L Langston; Tim Cundy; Rosemary Dargie; Malcolm G Dunlop; William D Fraser; Michael J Hooper; Gianluca Isaia; Geoff C Nicholson; Javier del Pino Montes; Rogelio Gonzalez-Sarmiento; Marco di Stefano; Albert Tenesa; John P Walsh; Stuart H Ralston

doi:10.1038/ng.562

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

Omar M E Albagha, Micaela R Visconti, Nerea Alonso, Anne L Langston, Tim Cundy, Rosemary Dargie, Malcolm G Dunlop, William D Fraser, Michael J Hooper, Gianluca Isaia, Geoff C Nicholson, Javier del Pino Montes, Rogelio Gonzalez-Sarmiento, Marco di Stefano, Albert Tenesa, John P Walsh, Stuart H Ralston

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240 Citations (Scopus)

Abstract

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 x 10(-24)). Significant associations were also observed with rs1561570 on 10p13 within the OPTN gene (P = 6.09 x 10(-13)) and with rs3018362 on 18q21 near the TNFRSF11A gene (P = 5.27 x 10(-13)). These studies provide new insights into the pathogenesis of PDB and identify OPTN, CSF1 and TNFRSF11A as candidate genes for disease susceptibility.

Original language	English
Pages (from-to)	520-524
Number of pages	5
Journal	Nature Genetics
Volume	42
Issue number	6
DOIs	https://doi.org/10.1038/ng.562
Publication status	Published - Jun 2010

Keywords

Genetic Loci
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Macrophage Colony-Stimulating Factor
Osteitis Deformans
Polymorphism, Single Nucleotide
Receptor Activator of Nuclear Factor-kappa B
Risk Factors
Transcription Factor TFIIIA

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10.1038/ng.562

Cite this

Albagha, O. M. E., Visconti, M. R., Alonso, N., Langston, A. L., Cundy, T., Dargie, R., Dunlop, M. G., Fraser, W. D., Hooper, M. J., Isaia, G., Nicholson, G. C., del Pino Montes, J., Gonzalez-Sarmiento, R., di Stefano, M., Tenesa, A., Walsh, J. P., & Ralston, S. H. (2010). Genome-wide association study identifies variants at CSF1, OPTN and TNFRSF11A as genetic risk factors for Paget's disease of bone. Nature Genetics, 42(6), 520-524. https://doi.org/10.1038/ng.562

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

abstract = "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 x 10(-24)). Significant associations were also observed with rs1561570 on 10p13 within the OPTN gene (P = 6.09 x 10(-13)) and with rs3018362 on 18q21 near the TNFRSF11A gene (P = 5.27 x 10(-13)). These studies provide new insights into the pathogenesis of PDB and identify OPTN, CSF1 and TNFRSF11A as candidate genes for disease susceptibility.",

keywords = "Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Macrophage Colony-Stimulating Factor, Osteitis Deformans, Polymorphism, Single Nucleotide, Receptor Activator of Nuclear Factor-kappa B, Risk Factors, Transcription Factor TFIIIA",

author = "Albagha, {Omar M E} and Visconti, {Micaela R} and Nerea Alonso and Langston, {Anne L} and Tim Cundy and Rosemary Dargie and Dunlop, {Malcolm G} and Fraser, {William D} and Hooper, {Michael J} and Gianluca Isaia and Nicholson, {Geoff C} and {del Pino Montes}, Javier and Rogelio Gonzalez-Sarmiento and {di Stefano}, Marco and Albert Tenesa and Walsh, {John P} and Ralston, {Stuart H}",

year = "2010",

month = jun,

doi = "10.1038/ng.562",

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Albagha, OME, Visconti, MR, Alonso, N, Langston, AL, Cundy, T, Dargie, R, Dunlop, MG, Fraser, WD, Hooper, MJ, Isaia, G, Nicholson, GC, del Pino Montes, J, Gonzalez-Sarmiento, R, di Stefano, M, Tenesa, A, Walsh, JP & Ralston, SH 2010, 'Genome-wide association study identifies variants at CSF1, OPTN and TNFRSF11A as genetic risk factors for Paget's disease of bone', Nature Genetics, vol. 42, no. 6, pp. 520-524. https://doi.org/10.1038/ng.562

TY - JOUR

T1 - Genome-wide association study identifies variants at CSF1, OPTN and TNFRSF11A as genetic risk factors for Paget's disease of bone

AU - Albagha, Omar M E

AU - Visconti, Micaela R

AU - Alonso, Nerea

AU - Langston, Anne L

AU - Cundy, Tim

AU - Dargie, Rosemary

AU - Dunlop, Malcolm G

AU - Fraser, William D

AU - Hooper, Michael J

AU - Isaia, Gianluca

AU - Nicholson, Geoff C

AU - del Pino Montes, Javier

AU - Gonzalez-Sarmiento, Rogelio

AU - di Stefano, Marco

AU - Tenesa, Albert

AU - Walsh, John P

AU - Ralston, Stuart H

PY - 2010/6

Y1 - 2010/6

N2 - 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 x 10(-24)). Significant associations were also observed with rs1561570 on 10p13 within the OPTN gene (P = 6.09 x 10(-13)) and with rs3018362 on 18q21 near the TNFRSF11A gene (P = 5.27 x 10(-13)). These studies provide new insights into the pathogenesis of PDB and identify OPTN, CSF1 and TNFRSF11A as candidate genes for disease susceptibility.

AB - 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 x 10(-24)). Significant associations were also observed with rs1561570 on 10p13 within the OPTN gene (P = 6.09 x 10(-13)) and with rs3018362 on 18q21 near the TNFRSF11A gene (P = 5.27 x 10(-13)). These studies provide new insights into the pathogenesis of PDB and identify OPTN, CSF1 and TNFRSF11A as candidate genes for disease susceptibility.

KW - Genetic Loci

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Humans

KW - Macrophage Colony-Stimulating Factor

KW - Osteitis Deformans

KW - Polymorphism, Single Nucleotide

KW - Receptor Activator of Nuclear Factor-kappa B

KW - Risk Factors

KW - Transcription Factor TFIIIA

U2 - 10.1038/ng.562

DO - 10.1038/ng.562

M3 - Article

C2 - 20436471

VL - 42

SP - 520

EP - 524

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 6

ER -