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

Marjolein J. Peters; Linda Broer; Hanneke L. D. M. Willemen; Gudny Eiriksdottir; Lynne J. Hocking; Kate L. Holliday; Michael A. Horan; Ingrid Meulenbelt; Tuhina Neogi; Maria Popham; Carsten O. Schmidt; Anushka Soni; Ana M. Valdes; Najaf Amin; Elaine M. Dennison; Niels Eijkelkamp; Tamara B. Harris; Deborah J. Hart; Albert Hofman; Frank J. P. M. Huygen; Karen A. Jameson; Gareth T. Jones; Lenore J. Launer; Hanneke J. M. Kerkhof; Marjolein de Kruijf; John McBeth; Margreet Kloppenburg; William E. Ollier; Ben Oostra; Antony Payton; Fernando Rivadeneira; Blair H. Smith; Albert V. Smith; Lisette Stolk; Alexander Teumer; Wendy Thomson; Andre G. Uitterlinden; Ke Wang; Sophie H. van Wingerden; Nigel K. Arden; Cyrus Cooper; David Felson; Vilmundur Gudnason; Gary J. Macfarlane; Neil Pendleton; P. Eline Slagboom; Tim D. Spector; Henry Voelzke; Annemieke Kavelaars; Cornelia M. van Duijn; Frances M. K. Williams; Joyce 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

Marjolein J. Peters, Linda Broer, Hanneke L. D. M. Willemen, Gudny Eiriksdottir, Lynne J. Hocking, Kate L. Holliday, Michael A. Horan, Ingrid Meulenbelt, Tuhina Neogi, Maria Popham, Carsten O. Schmidt, Anushka Soni, Ana M. Valdes, Najaf Amin, Elaine M. Dennison, Niels Eijkelkamp, Tamara B. Harris, Deborah J. Hart, Albert Hofman, Frank J. P. M. HuygenKaren A. Jameson, Gareth T. Jones, Lenore J. Launer, Hanneke J. M. Kerkhof, Marjolein de Kruijf, John McBeth, Margreet Kloppenburg, William E. Ollier, Ben Oostra, Antony Payton, Fernando Rivadeneira, Blair H. Smith, Albert V. Smith, Lisette Stolk, Alexander Teumer, Wendy Thomson, Andre G. Uitterlinden, Ke Wang, Sophie H. van Wingerden, Nigel K. Arden, Cyrus Cooper, David Felson, Vilmundur Gudnason, Gary J. Macfarlane, Neil Pendleton, P. Eline Slagboom, Tim D. Spector, Henry Voelzke, Annemieke Kavelaars, Cornelia M. van Duijn, Frances M. K. Williams, Joyce B. J. van Meurs^*

^*Corresponding author for this work

Twin Research & Genetic Epidemiology

Research output: Contribution to journal › Article › peer-review

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Abstract

Background and objectives Chronic widespread pain (CWP) is a common disorder affecting similar to 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=1.2x10(-8)). Combined with the replication, we observed a slightly attenuated OR of 1.17 (95% CI 1.10 to 1.24, p=4.7x10(-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=3.4x10(-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>7.7x10(-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
Article number	N/A
Pages (from-to)	427-436
Number of pages	10
Journal	Annals of the Rheumatic Diseases
Volume	72
Issue number	3
DOIs	https://doi.org/10.1136/annrheumdis-2012-201742
Publication status	Published - Mar 2013

Keywords

O-METHYLTRANSFERASE GENE
ADULT TWIN REGISTRY
KNEE OSTEOARTHRITIS
FIBROMYALGIA SYNDROME
T102C POLYMORPHISM
NEUROPATHIC PAIN
COHORT PROFILE
RISK-FACTORS
POPULATION
SUSCEPTIBILITY

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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. Article N/A. https://doi.org/10.1136/annrheumdis-2012-201742

@article{168a5987fc374f59b8b52802185ba97e,

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 similar to 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=1.2x10(-8)). Combined with the replication, we observed a slightly attenuated OR of 1.17 (95% CI 1.10 to 1.24, p=4.7x10(-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=3.4x10(-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>7.7x10(-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.",

keywords = "O-METHYLTRANSFERASE GENE, ADULT TWIN REGISTRY, KNEE OSTEOARTHRITIS, FIBROMYALGIA SYNDROME, T102C POLYMORPHISM, NEUROPATHIC PAIN, COHORT PROFILE, RISK-FACTORS, POPULATION, SUSCEPTIBILITY",

author = "Peters, {Marjolein J.} and Linda Broer and Willemen, {Hanneke L. D. M.} and Gudny Eiriksdottir and Hocking, {Lynne J.} and Holliday, {Kate L.} and Horan, {Michael A.} and Ingrid Meulenbelt and Tuhina Neogi and Maria Popham and Schmidt, {Carsten O.} and Anushka Soni and Valdes, {Ana M.} and Najaf Amin and Dennison, {Elaine M.} and Niels Eijkelkamp and Harris, {Tamara B.} and Hart, {Deborah J.} and Albert Hofman and Huygen, {Frank J. P. M.} and Jameson, {Karen A.} and Jones, {Gareth T.} and Launer, {Lenore J.} and Kerkhof, {Hanneke J. M.} and {de Kruijf}, Marjolein and John McBeth and Margreet Kloppenburg and Ollier, {William E.} and Ben Oostra and Antony Payton and Fernando Rivadeneira and Smith, {Blair H.} and Smith, {Albert V.} and Lisette Stolk and Alexander Teumer and Wendy Thomson and Uitterlinden, {Andre G.} and Ke Wang and {van Wingerden}, {Sophie H.} and Arden, {Nigel K.} and Cyrus Cooper and David Felson and Vilmundur Gudnason and Macfarlane, {Gary J.} and Neil Pendleton and Slagboom, {P. Eline} and Spector, {Tim D.} and Henry Voelzke and Annemieke Kavelaars and {van Duijn}, {Cornelia M.} and Williams, {Frances M. K.} and {van Meurs}, {Joyce 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",

}

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, Voelzke, 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, N/A, 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, Marjolein J.

AU - Broer, Linda

AU - Willemen, Hanneke L. D. M.

AU - Eiriksdottir, Gudny

AU - Hocking, Lynne J.

AU - Holliday, Kate L.

AU - Horan, Michael A.

AU - Meulenbelt, Ingrid

AU - Neogi, Tuhina

AU - Popham, Maria

AU - Schmidt, Carsten O.

AU - Soni, Anushka

AU - Valdes, Ana M.

AU - Amin, Najaf

AU - Dennison, Elaine M.

AU - Eijkelkamp, Niels

AU - Harris, Tamara B.

AU - Hart, Deborah J.

AU - Hofman, Albert

AU - Huygen, Frank J. P. M.

AU - Jameson, Karen A.

AU - Jones, Gareth T.

AU - Launer, Lenore J.

AU - Kerkhof, Hanneke J. M.

AU - de Kruijf, Marjolein

AU - McBeth, John

AU - Kloppenburg, Margreet

AU - Ollier, William E.

AU - Oostra, Ben

AU - Payton, Antony

AU - Rivadeneira, Fernando

AU - Smith, Blair H.

AU - Smith, Albert V.

AU - Stolk, Lisette

AU - Teumer, Alexander

AU - Thomson, Wendy

AU - Uitterlinden, Andre G.

AU - Wang, Ke

AU - van Wingerden, Sophie H.

AU - Arden, Nigel K.

AU - Cooper, Cyrus

AU - Felson, David

AU - Gudnason, Vilmundur

AU - Macfarlane, Gary J.

AU - Pendleton, Neil

AU - Slagboom, P. Eline

AU - Spector, Tim D.

AU - Voelzke, Henry

AU - Kavelaars, Annemieke

AU - van Duijn, Cornelia M.

AU - Williams, Frances M. K.

AU - van Meurs, Joyce B. J.

PY - 2013/3

Y1 - 2013/3

N2 - Background and objectives Chronic widespread pain (CWP) is a common disorder affecting similar to 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=1.2x10(-8)). Combined with the replication, we observed a slightly attenuated OR of 1.17 (95% CI 1.10 to 1.24, p=4.7x10(-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=3.4x10(-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>7.7x10(-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 similar to 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=1.2x10(-8)). Combined with the replication, we observed a slightly attenuated OR of 1.17 (95% CI 1.10 to 1.24, p=4.7x10(-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=3.4x10(-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>7.7x10(-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.

KW - O-METHYLTRANSFERASE GENE

KW - ADULT TWIN REGISTRY

KW - KNEE OSTEOARTHRITIS

KW - FIBROMYALGIA SYNDROME

KW - T102C POLYMORPHISM

KW - NEUROPATHIC PAIN

KW - COHORT PROFILE

KW - RISK-FACTORS

KW - POPULATION

KW - SUSCEPTIBILITY

U2 - 10.1136/annrheumdis-2012-201742

DO - 10.1136/annrheumdis-2012-201742

M3 - Article

SN - 0003-4967

VL - 72

SP - 427

EP - 436

JO - Annals of the Rheumatic Diseases

JF - Annals of the Rheumatic Diseases

IS - 3

M1 - N/A

ER -

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

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Keywords

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