An omics investigation into chronic widespread musculoskeletal pain reveals epiandrosterone sulfate as a potential biomarker

Chronic widespread musculoskeletal pain (CWP) is common, having a population prevalence of 10%. This study aimed to define the biological basis of the CWP/body mass association by using a systems biology approach. Adult female twins (n=2,444) from the TwinsUK registry who had extensive clinical, anthropometric, and "omic" data were included. Non-targeted metabolomics screening including 324 metabolites was carried out for CWP and body composition, assessed by DXA. The biological basis of these associations were explored through GWAS and replicated in an independent population sample (KORA study, n=2,483). A causal role for the genetic variants identified was sought in CWP using a Mendelian randomisation study design. Fat mass/height was the body composition variable most strongly associated with CWP (TwinsUK p=2.4x10 and KORA p=1.59x10). Of 324 metabolites examined, epiandrosterone sulphate (EAS) was highly associated with both CWP (p=1.05 x 10 in TwinsUK and p=3.70x10 in KORA) and fat mass/height. GWAS of EAS identified imputed SNP rs1581492 at 7q22.1 to be strikingly associated with EAS levels (p ≤2.49 x10) and this result was replicated in KORA (p=2.12x10). Mendelian randomization by rs1581492 genotype showed that EAS is unlikely to be causally related to CWP. Using an agnostic omics approach to focus on the association of CWP with BMI, we have confirmed a steroid hormone association and identified a genetic variant upstream of the CYP genes which likely controls this response. This study suggests that steroid hormone abnormalities result from pain rather than causing it, and EAS may provide a biomarker which identifies subgroups at risk of CWP.