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 4852%. 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=1.210 8 ). Combined with the replication, we observed a slightly attenuated OR of 1.17 (95% CI 1.10 to 1.24, p=4.710 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=3.410 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>7.710 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.

... 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=1.210 8 ). Combined with the replication, we observed a slightly attenuated OR of 1.17 (95% CI 1.10 to 1.24, p=4.710 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=3.410 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>7.710 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. Gene Polymorphism Fibromyalgis/Pain Syndromes Epidemiology special-feature unlocked Introduction Chronic widespread pain (CWP) is a

... Fam173b were measured in the spinal cord and the DRG. For more details, see the supplementary methods section. All experiments were performed in accordance with international guidelines and approved by the experimental animal committee of the University Medical Center Utrecht (carrageenan experiment) or the UK Home Office Animals (Scientific Procedures) Act 1986 (CFA experiment). Mice used for the carrageenan experiment were bred and maintained in the animal facility of the University of Utrecht (The

... upstream of the chaperonin-containing-TCP1-complex-5 gene (CCT5) and downstream of the FAMily with sequence similarity 173, member B gene (FAM173B) (rs13361160, p=1.210 8 and rs2386592, p=2.610 8 ). For both SNPs, the minor allele (MAF=43%) was associated with a 30% higher risk for CWP (OR=1.30, 95% CI 1.19 to 1.42). Figure 2 Genome-wide association results for chronic widespread pain (CWP) (stage 1). (A) Manhattan plot showing the p value of association tests for about 2 million SNPs with CWP in the

... allele frequency. Figure 3 Forest plot of the association of rs13361160 SNP with chronic widespread pain (CWP). Study specific estimates and summary association between rs13361160 and CWP are shown. This figure is only reproduced in colour in the online version. Functional analysis of rs13361160 and rs2386592 The SNPs rs13361160 and rs2386592 (r 2 =0.97) are annotated to the 5p15.2-region and located 81kb upstream of CCT5 and 57kb downstream of FAM173B ( figure 4 ). We tested whether rs13361160 and

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Gene: FAM173B - family with sequence similarity 173, member B - (NCBI)

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