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.
UR - http://www.scopus.com/inward/record.url?scp=84873744735&partnerID=8YFLogxK
U2 - 10.1136/annrheumdis-2012-201742
DO - 10.1136/annrheumdis-2012-201742
M3 - Article
C2 - 22956598
AN - SCOPUS:84873744735
SN - 0003-4967
VL - 72
SP - 427
EP - 436
JO - Annals of the Rheumatic Diseases
JF - Annals of the Rheumatic Diseases
IS - 3
ER -