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

Abstract

BackgroundChronic pain and asthma are associated, but the direction and basis of their genetic and biological relationship remain unclear. MethodsWe 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 (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. ResultsMultisite 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. ConclusionThese 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.