Multi-Omic Analyses Reveal Bidirectional Genetic Links and Convergent Inflammatory-Neuronal Signatures Between Frailty, Chronic Pain, and Rheumatoid Arthritis

Abstract Background: Frailty reflects reduced physiological resilience and increased vulnerability to stressors, functioning as a key biological marker of ageing. Yet, the molecular and causal mechanisms linking frailty to chronic inflammatory conditions remain unclear. Methods: We integrate Mendelian randomisation (MR), pairwise genome-wide association (PW-GWAS), and epigenetic-protein prediction to dissect bidirectional biological pathways between frailty, chronic pain (CP), and rheumatoid arthritis (RA). Results: Across nine genetically defined frailty phenotypes - six domain-specific factors, a general frailty factor (GF), and two cumulative indices (Frailty Index - FI, Fried Frailty Sco