Genome-wide association study meta-analysis of chronic widespread pain: evidence for involvement of the 5p15.2 region

M.J. Peters; L. Broer; H.L.D.M. Willemen; G. Eiriksdottir; L.J. Hocking; K.L. Holliday; M.A. Horan; I. Meulenbelt; T. Neogi; M. Popham; C.O. Schmidt; A. Soni; A.M. Valdes; N. Amin; E.M. Dennison; N. Eijkelkamp; T.B. Harris; D.J. Hart; A. Hofman; F.J.P.M. Huygen; K.A. Jameson; G.T. Jones; L.J. Launer; H.J.M. Kerkhof; M. De Kruijf; J. McBeth; M. Kloppenburg; W.E. Ollier; B. Oostra; A. Payton; F. Rivadeneira; Blair H Smith; A.V. Smith; L. Stolk; A. Teumer; W. Thomson; A.G. Uitterlinden; K. Wang; S.H. Van Wingerden; N.K. Arden; C. Cooper; D. Felson; V. Gudnason; G.J. Macfarlane; N. Pendleton; P.E. Slagboom; T.D. Spector; H. Völzke; A. Kavelaars; C.M. Van Duijn; F.M.K. Williams; J.B.J. Van Meurs

doi:10.1136/annrheumdis-2012-201742

Genome-wide association study meta-analysis of chronic widespread pain: evidence for involvement of the 5p15.2 region

M.J. Peters, L. Broer, H.L.D.M. Willemen, G. Eiriksdottir, L.J. Hocking, K.L. Holliday, M.A. Horan, I. Meulenbelt, T. Neogi, M. Popham, C.O. Schmidt, A. Soni, A.M. Valdes, N. Amin, E.M. Dennison, N. Eijkelkamp, T.B. Harris, D.J. Hart, A. Hofman, F.J.P.M. HuygenK.A. Jameson, G.T. Jones, L.J. Launer, H.J.M. Kerkhof, M. De Kruijf, J. McBeth, M. Kloppenburg, W.E. Ollier, B. Oostra, A. Payton, F. Rivadeneira, Blair H Smith, A.V. Smith, L. Stolk, A. Teumer, W. Thomson, A.G. Uitterlinden, K. Wang, S.H. Van Wingerden, N.K. Arden, C. Cooper, D. Felson, V. Gudnason, G.J. Macfarlane, N. Pendleton, P.E. Slagboom, T.D. Spector, H. Völzke, A. Kavelaars, C.M. Van Duijn, F.M.K. Williams, J.B.J. Van Meurs

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Abstract

BACKGROUND AND OBJECTIVES: Chronic widespread pain (CWP) is a common disorder affecting ~10% of the general population and has an estimated heritability of 48-52%. In the first large-scale genome-wide association study (GWAS) meta-analysis, we aimed to identify common genetic variants associated with CWP. METHODS: We conducted a GWAS meta-analysis in 1308 female CWP cases and 5791 controls of European descent, and replicated the effects of the genetic variants with suggestive evidence for association in 1480 CWP cases and 7989 controls. Subsequently, we studied gene expression levels of the nearest genes in two chronic inflammatory pain mouse models, and examined 92 genetic variants previously described associated with pain. RESULTS: The minor C-allele of rs13361160 on chromosome 5p15.2, located upstream of chaperonin-containing-TCP1-complex-5 gene (CCT5) and downstream of FAM173B, was found to be associated with a 30% higher risk of CWP (minor allele frequency=43%; OR=1.30, 95% CI 1.19 to 1.42, p=1.2×10(-8)). Combined with the replication, we observed a slightly attenuated OR of 1.17 (95% CI 1.10 to 1.24, p=4.7×10(-7)) with moderate heterogeneity (I2=28.4%). However, in a sensitivity analysis that only allowed studies with joint-specific pain, the combined association was genome-wide significant (OR=1.23, 95% CI 1.14 to 1.32, p=3.4×10(-8), I2=0%). Expression levels of Cct5 and Fam173b in mice with inflammatory pain were higher in the lumbar spinal cord, not in the lumbar dorsal root ganglions, compared to mice without pain. None of the 92 genetic variants previously described were significantly associated with pain (p>7.7×10(-4)). CONCLUSIONS: We identified a common genetic variant on chromosome 5p15.2 associated with joint-specific CWP in humans. This work suggests that CCT5 and FAM173B are promising targets in the regulation of pain.

Original language	English
Pages (from-to)	427-436
Number of pages	10
Journal	Annals of the Rheumatic Diseases
Volume	72
Issue number	3
Early online date	6 Sept 2012
DOIs	https://doi.org/10.1136/annrheumdis-2012-201742
Publication status	Published - Mar 2013

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Peters, M. J., Broer, L., Willemen, H. L. D. M., Eiriksdottir, G., Hocking, L. J., Holliday, K. L., Horan, M. A., Meulenbelt, I., Neogi, T., Popham, M., Schmidt, C. O., Soni, A., Valdes, A. M., Amin, N., Dennison, E. M., Eijkelkamp, N., Harris, T. B., Hart, D. J., Hofman, A., ... Van Meurs, J. B. J. (2013). Genome-wide association study meta-analysis of chronic widespread pain: evidence for involvement of the 5p15.2 region. Annals of the Rheumatic Diseases, 72(3), 427-436. https://doi.org/10.1136/annrheumdis-2012-201742

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title = "Genome-wide association study meta-analysis of chronic widespread pain: evidence for involvement of the 5p15.2 region",

abstract = "BACKGROUND AND OBJECTIVES: Chronic widespread pain (CWP) is a common disorder affecting ~10% of the general population and has an estimated heritability of 48-52%. In the first large-scale genome-wide association study (GWAS) meta-analysis, we aimed to identify common genetic variants associated with CWP. METHODS: We conducted a GWAS meta-analysis in 1308 female CWP cases and 5791 controls of European descent, and replicated the effects of the genetic variants with suggestive evidence for association in 1480 CWP cases and 7989 controls. Subsequently, we studied gene expression levels of the nearest genes in two chronic inflammatory pain mouse models, and examined 92 genetic variants previously described associated with pain. RESULTS: The minor C-allele of rs13361160 on chromosome 5p15.2, located upstream of chaperonin-containing-TCP1-complex-5 gene (CCT5) and downstream of FAM173B, was found to be associated with a 30% higher risk of CWP (minor allele frequency=43%; OR=1.30, 95% CI 1.19 to 1.42, p=1.2×10(-8)). Combined with the replication, we observed a slightly attenuated OR of 1.17 (95% CI 1.10 to 1.24, p=4.7×10(-7)) with moderate heterogeneity (I2=28.4%). However, in a sensitivity analysis that only allowed studies with joint-specific pain, the combined association was genome-wide significant (OR=1.23, 95% CI 1.14 to 1.32, p=3.4×10(-8), I2=0%). Expression levels of Cct5 and Fam173b in mice with inflammatory pain were higher in the lumbar spinal cord, not in the lumbar dorsal root ganglions, compared to mice without pain. None of the 92 genetic variants previously described were significantly associated with pain (p>7.7×10(-4)). CONCLUSIONS: We identified a common genetic variant on chromosome 5p15.2 associated with joint-specific CWP in humans. This work suggests that CCT5 and FAM173B are promising targets in the regulation of pain.",

author = "M.J. Peters and L. Broer and H.L.D.M. Willemen and G. Eiriksdottir and L.J. Hocking and K.L. Holliday and M.A. Horan and I. Meulenbelt and T. Neogi and M. Popham and C.O. Schmidt and A. Soni and A.M. Valdes and N. Amin and E.M. Dennison and N. Eijkelkamp and T.B. Harris and D.J. Hart and A. Hofman and F.J.P.M. Huygen and K.A. Jameson and G.T. Jones and L.J. Launer and H.J.M. Kerkhof and {De Kruijf}, M. and J. McBeth and M. Kloppenburg and W.E. Ollier and B. Oostra and A. Payton and F. Rivadeneira and Smith, {Blair H} and A.V. Smith and L. Stolk and A. Teumer and W. Thomson and A.G. Uitterlinden and K. Wang and {Van Wingerden}, S.H. and N.K. Arden and C. Cooper and D. Felson and V. Gudnason and G.J. Macfarlane and N. Pendleton and P.E. Slagboom and T.D. Spector and H. V{\"o}lzke and A. Kavelaars and {Van Duijn}, C.M. and F.M.K. Williams and {Van Meurs}, J.B.J.",

year = "2013",

month = mar,

doi = "10.1136/annrheumdis-2012-201742",

language = "English",

volume = "72",

pages = "427--436",

journal = "Annals of the Rheumatic Diseases",

issn = "0003-4967",

publisher = "BMJ Publishing Group",

number = "3",

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Peters, MJ, Broer, L, Willemen, HLDM, Eiriksdottir, G, Hocking, LJ, Holliday, KL, Horan, MA, Meulenbelt, I, Neogi, T, Popham, M, Schmidt, CO, Soni, A, Valdes, AM, Amin, N, Dennison, EM, Eijkelkamp, N, Harris, TB, Hart, DJ, Hofman, A, Huygen, FJPM, Jameson, KA, Jones, GT, Launer, LJ, Kerkhof, HJM, De Kruijf, M, McBeth, J, Kloppenburg, M, Ollier, WE, Oostra, B, Payton, A, Rivadeneira, F, Smith, BH, Smith, AV, Stolk, L, Teumer, A, Thomson, W, Uitterlinden, AG, Wang, K, Van Wingerden, SH, Arden, NK, Cooper, C, Felson, D, Gudnason, V, Macfarlane, GJ, Pendleton, N, Slagboom, PE, Spector, TD, Völzke, H, Kavelaars, A, Van Duijn, CM, Williams, FMK & Van Meurs, JBJ 2013, 'Genome-wide association study meta-analysis of chronic widespread pain: evidence for involvement of the 5p15.2 region', Annals of the Rheumatic Diseases, vol. 72, no. 3, pp. 427-436. https://doi.org/10.1136/annrheumdis-2012-201742

TY - JOUR

T1 - Genome-wide association study meta-analysis of chronic widespread pain

T2 - evidence for involvement of the 5p15.2 region

AU - Peters, M.J.

AU - Broer, L.

AU - Willemen, H.L.D.M.

AU - Eiriksdottir, G.

AU - Hocking, L.J.

AU - Holliday, K.L.

AU - Horan, M.A.

AU - Meulenbelt, I.

AU - Neogi, T.

AU - Popham, M.

AU - Schmidt, C.O.

AU - Soni, A.

AU - Valdes, A.M.

AU - Amin, N.

AU - Dennison, E.M.

AU - Eijkelkamp, N.

AU - Harris, T.B.

AU - Hart, D.J.

AU - Hofman, A.

AU - Huygen, F.J.P.M.

AU - Jameson, K.A.

AU - Jones, G.T.

AU - Launer, L.J.

AU - Kerkhof, H.J.M.

AU - De Kruijf, M.

AU - McBeth, J.

AU - Kloppenburg, M.

AU - Ollier, W.E.

AU - Oostra, B.

AU - Payton, A.

AU - Rivadeneira, F.

AU - Smith, Blair H

AU - Smith, A.V.

AU - Stolk, L.

AU - Teumer, A.

AU - Thomson, W.

AU - Uitterlinden, A.G.

AU - Wang, K.

AU - Van Wingerden, S.H.

AU - Arden, N.K.

AU - Cooper, C.

AU - Felson, D.

AU - Gudnason, V.

AU - Macfarlane, G.J.

AU - Pendleton, N.

AU - Slagboom, P.E.

AU - Spector, T.D.

AU - Völzke, H.

AU - Kavelaars, A.

AU - Van Duijn, C.M.

AU - Williams, F.M.K.

AU - Van Meurs, J.B.J.

PY - 2013/3

Y1 - 2013/3

N2 - BACKGROUND AND OBJECTIVES: Chronic widespread pain (CWP) is a common disorder affecting ~10% of the general population and has an estimated heritability of 48-52%. In the first large-scale genome-wide association study (GWAS) meta-analysis, we aimed to identify common genetic variants associated with CWP. METHODS: We conducted a GWAS meta-analysis in 1308 female CWP cases and 5791 controls of European descent, and replicated the effects of the genetic variants with suggestive evidence for association in 1480 CWP cases and 7989 controls. Subsequently, we studied gene expression levels of the nearest genes in two chronic inflammatory pain mouse models, and examined 92 genetic variants previously described associated with pain. RESULTS: The minor C-allele of rs13361160 on chromosome 5p15.2, located upstream of chaperonin-containing-TCP1-complex-5 gene (CCT5) and downstream of FAM173B, was found to be associated with a 30% higher risk of CWP (minor allele frequency=43%; OR=1.30, 95% CI 1.19 to 1.42, p=1.2×10(-8)). Combined with the replication, we observed a slightly attenuated OR of 1.17 (95% CI 1.10 to 1.24, p=4.7×10(-7)) with moderate heterogeneity (I2=28.4%). However, in a sensitivity analysis that only allowed studies with joint-specific pain, the combined association was genome-wide significant (OR=1.23, 95% CI 1.14 to 1.32, p=3.4×10(-8), I2=0%). Expression levels of Cct5 and Fam173b in mice with inflammatory pain were higher in the lumbar spinal cord, not in the lumbar dorsal root ganglions, compared to mice without pain. None of the 92 genetic variants previously described were significantly associated with pain (p>7.7×10(-4)). CONCLUSIONS: We identified a common genetic variant on chromosome 5p15.2 associated with joint-specific CWP in humans. This work suggests that CCT5 and FAM173B are promising targets in the regulation of pain.

AB - BACKGROUND AND OBJECTIVES: Chronic widespread pain (CWP) is a common disorder affecting ~10% of the general population and has an estimated heritability of 48-52%. In the first large-scale genome-wide association study (GWAS) meta-analysis, we aimed to identify common genetic variants associated with CWP. METHODS: We conducted a GWAS meta-analysis in 1308 female CWP cases and 5791 controls of European descent, and replicated the effects of the genetic variants with suggestive evidence for association in 1480 CWP cases and 7989 controls. Subsequently, we studied gene expression levels of the nearest genes in two chronic inflammatory pain mouse models, and examined 92 genetic variants previously described associated with pain. RESULTS: The minor C-allele of rs13361160 on chromosome 5p15.2, located upstream of chaperonin-containing-TCP1-complex-5 gene (CCT5) and downstream of FAM173B, was found to be associated with a 30% higher risk of CWP (minor allele frequency=43%; OR=1.30, 95% CI 1.19 to 1.42, p=1.2×10(-8)). Combined with the replication, we observed a slightly attenuated OR of 1.17 (95% CI 1.10 to 1.24, p=4.7×10(-7)) with moderate heterogeneity (I2=28.4%). However, in a sensitivity analysis that only allowed studies with joint-specific pain, the combined association was genome-wide significant (OR=1.23, 95% CI 1.14 to 1.32, p=3.4×10(-8), I2=0%). Expression levels of Cct5 and Fam173b in mice with inflammatory pain were higher in the lumbar spinal cord, not in the lumbar dorsal root ganglions, compared to mice without pain. None of the 92 genetic variants previously described were significantly associated with pain (p>7.7×10(-4)). CONCLUSIONS: We identified a common genetic variant on chromosome 5p15.2 associated with joint-specific CWP in humans. This work suggests that CCT5 and FAM173B are promising targets in the regulation of pain.

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U2 - 10.1136/annrheumdis-2012-201742

DO - 10.1136/annrheumdis-2012-201742

M3 - Article

C2 - 22956598

SN - 0003-4967

VL - 72

SP - 427

EP - 436

JO - Annals of the Rheumatic Diseases

JF - Annals of the Rheumatic Diseases

IS - 3

ER -

Genome-wide association study meta-analysis of chronic widespread pain: evidence for involvement of the 5p15.2 region

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