Dataset Information

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.

SUBMITTER: Peters MJ

PROVIDER: S-EPMC3691951 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundChronic widespread pain (CWP) including fibromyalgia has a prevalence of up to 15% and is associated with substantial morbidity. Supporting psychosocial and behavioural self-management is increasingly important for CWP, as pharmacological interventions show limited benefit. We systematically reviewed the effectiveness of interventions applying self-management principles for CWP including fibromyalgia.MethodsMEDLINE, Embase, PsycINFO, The Cochrane Central Register of Controlled Trials and the WHO International Clinical Trials Registry were searched for studies reporting randomised controlled trials of interventions adhering to self-management principles for CWP including fibromyalgia. Primary outcomes included physical function and pain intensity. Where data were sufficient, meta-analysis was conducted using a random effects model. Studies were narratively reviewed where meta-analysis could not be conducted Evidence quality was rated using GRADE (Grading of Recommendations, Assessment, Development and Evaluations) (PROSPERO-CRD42018099212).ResultsThirty-nine completed studies were included. Despite some variability in studies narratively reviewed, in studies meta-analysed self-management interventions improved physical function in the short-term, post-treatment to 3 months (SMD 0.42, 95% CI 0.20, 0.64) and long-term, post 6 months (SMD 0.36, 95% CI 0.20, 0.53), compared to no treatment/usual care controls. Studies reporting on pain narratively had greater variability, however, those studies meta-analysed showed self-management interventions reduced pain in the short-term (SMD -0.49, 95% CI -0.70, -0.27) and long-term (SMD -0.38, 95% CI -0.58, -0.19) compared to no treatment/usual care. There were few differences in physical function and pain when self-management interventions were compared to active interventions. The quality of the evidence was rated as low.ConclusionReviewed studies suggest self-management interventions can be effective in improving physical function and reducing pain in the short and long-term for CWP including fibromyalgia. However, the quality of evidence was low. Future research should address quality issues whilst making greater use of theory and patient involvement to understand reported variability.

Project description:Chronic pain is highly prevalent worldwide and represents a significant socioeconomic and public health burden. Several aspects of chronic pain, for example back pain and a severity-related phenotype 'chronic pain grade', have been shown previously to be complex heritable traits with a polygenic component. Additional pain-related phenotypes capturing aspects of an individual's overall sensitivity to experiencing and reporting chronic pain have also been suggested as a focus for investigation. We made use of a measure of the number of sites of chronic pain in individuals within the UK general population. This measure, termed Multisite Chronic Pain (MCP), is a complex trait and its genetic architecture has not previously been investigated. To address this, we carried out a large-scale genome-wide association study (GWAS) of MCP in ~380,000 UK Biobank participants. Our findings were consistent with MCP having a significant polygenic component, with a Single Nucleotide Polymorphism (SNP) heritability of 10.2%. In total 76 independent lead SNPs at 39 risk loci were associated with MCP. Additional gene-level association analyses identified neurogenesis, synaptic plasticity, nervous system development, cell-cycle progression and apoptosis genes as enriched for genetic association with MCP. Genetic correlations were observed between MCP and a range of psychiatric, autoimmune and anthropometric traits, including major depressive disorder (MDD), asthma and Body Mass Index (BMI). Furthermore, in Mendelian randomisation (MR) analyses a causal effect of MCP on MDD was observed. Additionally, a polygenic risk score (PRS) for MCP was found to significantly predict chronic widespread pain (pain all over the body), indicating the existence of genetic variants contributing to both of these pain phenotypes. Overall, our findings support the proposition that chronic pain involves a strong nervous system component with implications for our understanding of the physiology of chronic pain. These discoveries may also inform the future development of novel treatment approaches.