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

Abstract

Chronic pain and asthma are associated, but the direction and basis of their genetic and biological relationship remain unclear. We conducted genome-wide association studies (GWAS), multi-trait analysis of GWAS (MTAG), polygenic risk score (PRS) prediction, bivariate causal modelling, and Mendelian randomisation (MR) across nine chronic pain traits and three asthma age-of-onset strata (<18, 18-40, and >40 yr for childhood-, adult-, and late-onset asthma, respectively) in 456 958 UK Biobank and 25 275 Canadian Longitudinal Study on Aging participants of European descent. We analysed shared and distinct genetic architecture using gene-, pathway-, tissue-, and cell-type-based enrichment analyses. Multisite chronic pain (MCP) showed the strongest and most consistent genetic overlap with asthma, with genetic correlation increasing from childhood (r_g=0.01) to late-onset asthma (r_g=0.40). Estimated causal variants for late-onset asthma (∼1.8 K), and fewer for childhood asthma (∼0.2 K), were nested within a broader MCP profile (∼9.4 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 using MTAG, and uncovered genes enriched for immune and CNS function across pathways, tissues, and cell types. In contrast, childhood asthma showed immune-specific enrichment alone. These findings reveal neurological function linking chronic pain to late-onset asthma, distinct from childhood asthma, and highlight a CNS contribution to asthma emerging later in life.