Common factor GWAS identifies shared risk loci between chronic widespread pain, atherosclerosis and arterial stiffness

Introduction Chronic widespread pain (CWP) is a complex condition linked to impaired arterial health, including atherosclerosis and increased arterial stiffness. Epidemiological evidence suggests shared biological mechanisms, with strong associations between CWP and arterial dysfunction. However, the genetic basis remains largely unexplored. Methods We conducted a common pathway genome-wide association study using genomic structural equation modelling (GenomicSEM) and genome-wide association studies (GWAS) summary statistics for CWP, atherosclerosis and pulse wave velocity to identify shared genetic factors. Results This analysis revealed 53 genome-wide significant variants contributing to a shared latent factor, with opposing trait loadings suggestive of antagonistic pleiotropy. Lead loci included RNF123, ATP2C1 and COMT, with gene-level analysis implicating neurodevelopmental pathways and glycosaminoglycan degradation through hyaluronidase activity. Chromatin interaction and expression mapping supported regulatory links in relevant tissues. Conclusions Our findings demonstrate that neurogenic and extracellular matrix-related processes, including glycan metabolism, contribute to the shared genetic architecture of CWP and cardiovascular traits, offering mechanistic insight into their comorbidity.