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 Score - FFS) - MR revealed widespread causal effects of CP and RA on frailty. Genetic liability to higher chronic pain robustly increased frailty severity across the cumulative frailty measures (FI and FFS) and the disability-related frailty domain (F6), with the strongest effect observed for the Frailty Index ({beta} = 0.70, p = 7.9 x 10-52), while cumulative frailty also elevated pain risk ({beta} = 0.37, p = 2.6 x 10-13), supporting a reciprocal feedback model. RA exerted more selective effects, increasing cumulative frailty (FI and FFS) and disability-related frailty (F6), whereas the general frailty factor increased RA susceptibility (OR = 4.59, p = 9.5 x 10-8). Notably, the multimorbidity-related frailty domain showed an inverse effect on RA risk (OR = 0.65, p = 0.0078), suggesting immune adaptation or exhaustion within advanced frailty states. PW-GWAS and fine-mapping revealed shared causal loci linking inflammation, metabolism, and neurostructural pathways - SLC39A8, NLGN1, IL2RA, ERBB3, and MAGI3 - highlighting neuroimmune and synaptic processes as convergent ageing pathways. Epigenetic-proteomic analyses further identified two opposing axes: inflammatory and complement proteins (CRP, C5, CCL18, STC1) positively associated with frailty, versus neuronal adhesion and extracellular matrix (ECM) proteins (NCAM1, CNTN4, NTRK3, ADAMTS13) conferring resilience. Conclusion: Together, these findings redefine frailty as a biologically dynamic interface between inflammation and structural maintenance, where opposing molecular pathways shape vulnerability and resilience. This integrative framework highlights frailty as both a biomarker and potential intervention target, linking inflammatory dysregulation to modifiable trajectories of functional ageing.