Novel Calcium Regulation Gene Identified as Having Causal Role in Chronic Widespread Musculoskeletal Pain

A female massage therapist standing behind a male patient and massaging his back with both hands.
A team of researchers conducted a genome-wide association study to gain insight into the genetics of chronic widespread pain

A locus involved with calcium regulation was associated with chronic widespread musculoskeletal pain (CWP). These findings were published in the Annals of the Rheumatic Diseases.

For this study, researchers used discovery (UK Biobank) and validation (TwinsUK, The English Longitudinal Study of Ageing, The Rotterdam Study 1, 2, 3, and Nord-Trøndelag Health Survey) cohorts comprising individuals with CWP (n=21,091) and control group participants (n=271,832) to perform a genome-wide association study. CWP was defined in the discovery sample as self-reported body-wide pain lasting for more than 3 months.

Among most datasets, individuals with CWP were skewed toward women who were older with a higher body mass index (BMI).

A total of 3 loci (rs1491985, rs10490825, rs165599) reached genome-wide significance (P <5´10-8) in the discovery set. Compared with the heritability of CWP, these 3 variants explained 33% of the variance in CWP risk.

These identified genes were ring finger protein 123 (RNF123; P =1.6´10-8), ATPase secretory pathway Ca2+ transporting 1 (ATP2C1; P =1.3´10-8), and catechol-O-methyltransferase (COMT; P =2.5´10-8).

In the meta-analysis validation dataset, the first loci, rs1491985 (RNF123), replicated at a significance of P =.0002; rs10490825 (ATP2C1) trended toward significance but did not meet the cutoff (P =.0227); and rs165599 (COMT) failed to replicate (P =.7300). None of the 3 loci were validated directionally, in which the protective allele identified in the discovery cohort was the risk loci in the validation analysis.

These loci were related with expression quantitative trait loci and 89 related genes were identified. In tissue-specific analyses of identified sets of possible causative genes for CWP, expression was more enriched in skeletal muscle tissues than any other tissue types.

Genetic correlations between CWP and 23 other phenotypic traits were observed. The most highly correlated phenotypes in the positive and negative directions were depression (r, 0.65) and educational attainment (r, -0.61), respectively.

This study may have been limited by the self-reported definition of CWP.

This study identified a novel locus that may have a causative role in CWP (RNF123). The top 2 genes identified had a role in calcium regulation, and the set of expression quantitative trait loci genes were enriched in skeletal muscle. One of the most studied genes for its role in CWP, COMT, was not replicated in this analysis.

Disclosure: One study author declared affiliations with industry. Please refer to the original reference for a full list of disclosures.


Rahman MS, Winsvold BS, Chavez Chavez SO, et al. Genome-wide association study identifies RNF123 locus as associated with chronic widespread musculoskeletal pain. Ann Rheum Dis. Published online April 29, 2021. doi:10.1136/annrheumdis-2020-219624