Genome-wide association study identifies RNF123 locus as associated with chronic widespread musculoskeletal pain

Background and ObjectivesChronic widespread musculoskeletal pain (CWP) is a symptom of fibromyalgia and a complex trait with poorly understood pathogenesis. CWP is heritable (48-54%), but its genetic architecture is unknown and candidate gene studies have produced inconsistent results. We conducted a genome-wide association study to get insight into the genetic background of CWP. MethodsNorthern Europeans from UK Biobank comprising 6,914 cases reporting pain all over the body lasting more than 3 months and 242,929 controls were studied. Replication of three lead genome-wide significant single nucleotide polymorphisms (SNPs) was attempted in 6 independent European cohorts (N=43,080; cases=14,177). Genetic correlations with risk factors, tissue specificity, and colocalization were examined. ResultsThree genome-wide significant loci were identified (rs1491985, rs10490825, rs165599) residing within the genes RNF123, ATP2C1, and COMT. The RNF123 locus was replicated (meta-analysis p=0.0002), the ATP2C1 locus showed suggestive association (p=0.0227), and the COMT locus was not replicated. Partial genetic correlation between CWP and depressive symptoms, body mass index, age of first birth, and years of schooling were identified. Tissue specificity and colocalization analysis highlight the relevance of skeletal muscle in CWP. ConclusionsWe report a novel association of RNF123 locus with CWP and suggest a role of ATP2C1, consistent with a role of calcium regulation in CWP. The association to COMT, one of the most studied genes in chronic pain field, was not confirmed in the replication analysis. Key messagesO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LIChronic widespread musculoskeletal pain (CWP) is a primary diagnostic feature of fibromyalgia. C_LIO_LICWP is moderately heritable, but precise genes involved in the pathogenesis of CWP are yet to be identified. C_LI What does this study add?O_LIThis is the largest genetic study conducted on CWP to date and identified novel genetic risk loci (RNF123 and ATP2C1). C_LIO_LIThe genetic signal points to peripheral pain mechanisms in CWP, and shows genetic correlation with other traits, including BMI and depression. C_LI How might this impact on clinical practice or future developments?O_LIThe findings add to etiological basis of CWP. C_LI