Cross-trait genetic analysis of osteoarthritis and fibromyalgia implicates ferroptosis and potential therapeutic targets

An epidemiological association between osteoarthritis (OA) and fibromyalgia (FM) has been reported, but whether this reflect a shared genetic architecture and correlation remains unclear. We used large-scale genome-wide association study (GWAS) summary data utilizing Linkage disequilibrium score regression (LDSC) analysis, Multimarker Analysis of GenoMic Annotation (MAGMA) analysis, fine-mapping, co-localization analysis and functional enrichment to investigate the relationship between OA and FM. Multiple validations were used to evaluate our results. To investigate potential intermolecular interactions between potential target drug and overlapping core target protein, molecular docking analyses were performed. We find a significantly greater genetic correlation between these two traits and identify 17 significant SNPs (including 2 novel SNPs) and corresponding genes shared between OA and FM. Bayesian linear regression confirmed the effect of these shared SNPs on joint OA-FM phenotype. Fine-mapping highlighted a variant with a high causal probability for OA, implicating a shared genetic hub. The identified genes and gene sets significantly converged on the ferroptosis pathway for the joint OA-FM phenotype. Molecular docking verified strong binding affinity between overlapping core target protein Coenzyme Q10 (CoQ10) or vitamin E. Our study suggested that OA patients with SLC39A8 might benefit from early screening for FM or arthritis pain due to central sensitization based on shared genetic architecture. Based on the identified ferroptosis pathway and molecular docking, our study suggested CoQ10 and vitamin E may be beneficial to joint OA-FM phenotype and may relive the chronic pain due to central sensitization for OA patients. Our study suggests that OA patients with SLC39A8 might benefit from early screening for FM or arthritis pain due to central sensitization based on shared genetic architecture. Moreover, based on the identified ferroptosis pathway and molecular docking, our study suggested Coenzyme Q10 (CoQ10) and vitamin E may be beneficial to joint OA-FM phenotype and may relive the chronic pain due to central sensitization for OA patients.