Causal evidence linking chronic pain genetics to late-onset asthma via the nervous system

Background: Chronic pain and asthma are associated, but the direction and basis of their genetic and biological relationship remain unclear. Methods: We conducted genome–wide association (GWA), cross–trait meta–analysis, polygenic risk score (PRS) prediction, bivariate causal modeling, and Mendelian randomization (MR) across nine chronic pain traits and three asthma age–of–onset strata (<18, 18–40, and >40 years for childhood, adult, and late–onset asthma) in 456,958 UK Biobank (UKB) and 25,275 Canadian Longitudinal Study on Aging (CLSA) participants of European descent. We analyzed shared and distinct genetic architecture using gene, pathway, tissue, and cell–type–based enrichment analyses. Results: Multisite chronic pain (MCP) showed the strongest and most consistent genetic overlap with asthma, with genetic correlation increasing from childhood (rg = 0.01) to late–onset asthma (rg = 0.40). Estimated causal variants for late–onset asthma (1.8 K) were nested within a broader MCP profile (9.4 K), with fewer for childhood asthma (0.2 K). Using PRS, MR, and longitudinal analyses, we found that MCP contributes causally to late–onset asthma. Top causal variants from MR mapped to GMPPB–RNF123, DCC, and FOXP2. Conditioning by MCP amplified late–onset asthma variant effect sizes and uncovered genes enriched for immune and central nervous system pathways, tissues, and cell types. In contrast, childhood asthma showed immune–specific enrichment alone. Conclusion: These findings reveal neurological function linking chronic pain to late–onset asthma, distinct from childhood asthma, and highlight a central nervous system contribution to asthma emerging later in life.