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 & 32 others 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, André 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 Völzke, Annemieke Kavelaars, Cornelia M van Duijn, Frances M K Williams, Joyce 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 languageEnglish
Pages (from-to)427-436
Number of pages10
JournalAnnals of the Rheumatic Diseases
Volume72
Issue number3
Early online date6 Sep 2012
DOIs
Publication statusPublished - Mar 2013

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Genome-Wide Association Study
Chronic Pain
Meta-Analysis
Genes
Chaperonins
Pain
Chromosomes
Spinal Cord
Gene expression
Arthralgia
Spinal Ganglia
Sensitivity analysis
Gene Frequency
Joints
Alleles
Genome
Gene Expression
Population

Cite this

Peters, M. J., Broer, L., Willemen, H. L. D. M., Eiriksdottir, G., Hocking, L. J., Holliday, K. L., ... 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

Genome-wide association study meta-analysis of chronic widespread pain : evidence for involvement of the 5p15.2 region. / Peters, Marjolein J; Broer, Linda; Willemen, Hanneke L D M; Eiriksdottir, Gudny; Hocking, Lynne J; Holliday, Kate L; Horan, Michael A; Meulenbelt, Ingrid; Neogi, Tuhina; Popham, Maria; Schmidt, Carsten O; Soni, Anushka; Valdes, Ana M; Amin, Najaf; Dennison, Elaine M; Eijkelkamp, Niels; Harris, Tamara B; Hart, Deborah J; Hofman, Albert; Huygen, Frank J P M; Jameson, Karen A; Jones, Gareth T; Launer, Lenore J; Kerkhof, Hanneke J M; de Kruijf, Marjolein; McBeth, John; Kloppenburg, Margreet; Ollier, William E; Oostra, Ben; Payton, Antony; Rivadeneira, Fernando; Smith, Blair H; Smith, Albert V; Stolk, Lisette; Teumer, Alexander; Thomson, Wendy; Uitterlinden, André G; Wang, Ke; van Wingerden, Sophie H; Arden, Nigel K; Cooper, Cyrus; Felson, David; Gudnason, Vilmundur; Macfarlane, Gary J; Pendleton, Neil; Slagboom, P Eline; Spector, Tim D; Völzke, Henry; Kavelaars, Annemieke; van Duijn, Cornelia M; Williams, Frances M K; van Meurs, Joyce B J.

In: Annals of the Rheumatic Diseases, Vol. 72, No. 3, 03.2013, p. 427-436.

Research output: Contribution to journalArticle

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
Peters, Marjolein J ; Broer, Linda ; Willemen, Hanneke L D M ; Eiriksdottir, Gudny ; Hocking, Lynne J ; Holliday, Kate L ; Horan, Michael A ; Meulenbelt, Ingrid ; Neogi, Tuhina ; Popham, Maria ; Schmidt, Carsten O ; Soni, Anushka ; Valdes, Ana M ; Amin, Najaf ; Dennison, Elaine M ; Eijkelkamp, Niels ; Harris, Tamara B ; Hart, Deborah J ; Hofman, Albert ; Huygen, Frank J P M ; Jameson, Karen A ; Jones, Gareth T ; Launer, Lenore J ; Kerkhof, Hanneke J M ; de Kruijf, Marjolein ; McBeth, John ; Kloppenburg, Margreet ; Ollier, William E ; Oostra, Ben ; Payton, Antony ; Rivadeneira, Fernando ; Smith, Blair H ; Smith, Albert V ; Stolk, Lisette ; Teumer, Alexander ; Thomson, Wendy ; Uitterlinden, André G ; Wang, Ke ; van Wingerden, Sophie H ; Arden, Nigel K ; Cooper, Cyrus ; Felson, David ; Gudnason, Vilmundur ; Macfarlane, Gary J ; Pendleton, Neil ; Slagboom, P Eline ; Spector, Tim D ; Völzke, Henry ; Kavelaars, Annemieke ; van Duijn, Cornelia M ; Williams, Frances M K ; van Meurs, Joyce B J. / Genome-wide association study meta-analysis of chronic widespread pain : evidence for involvement of the 5p15.2 region. In: Annals of the Rheumatic Diseases. 2013 ; Vol. 72, No. 3. pp. 427-436.
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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 = "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, {Andr{\'e} 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 V{\"o}lzke and Annemieke Kavelaars and {van Duijn}, {Cornelia M} and Williams, {Frances M K} and {van Meurs}, {Joyce B J}",
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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, André 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 - Völzke, 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 ~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.

U2 - 10.1136/annrheumdis-2012-201742

DO - 10.1136/annrheumdis-2012-201742

M3 - Article

VL - 72

SP - 427

EP - 436

JO - Annals of the Rheumatic Diseases

JF - Annals of the Rheumatic Diseases

SN - 0003-4967

IS - 3

ER -