{"doi":"10.1101/2025.08.08.25333309","title":"Causal evidence linking chronic pain genetics to late-onset asthma via the nervous system","abstract":"Abstract 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.","journal":"medRxiv","year":2025,"id":572275,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9401,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":52763,"name":"Marc Parisien","orcid":"0000-0003-2924-5960","position":1,"is_corresponding":false},{"id":1478477,"name":"Matt Fillingim","orcid":"0000-0002-4774-1565","position":2,"is_corresponding":false},{"id":1478920,"name":"C.X. Chen","orcid":null,"position":3,"is_corresponding":false},{"id":1478478,"name":"Yiran Chen","orcid":"0000-0002-4602-2454","position":4,"is_corresponding":false},{"id":1478479,"name":"N. Dimitrov","orcid":"0000-0002-1016-9788","position":5,"is_corresponding":false},{"id":1083034,"name":"Maha Zidan","orcid":null,"position":6,"is_corresponding":false},{"id":1478921,"name":"Loveni Hanumunthadu","orcid":null,"position":7,"is_corresponding":false},{"id":1478480,"name":"Peter Her","orcid":"0000-0003-3481-6123","position":8,"is_corresponding":false},{"id":304547,"name":"Sahir Bhatnagar","orcid":"0000-0001-8956-2509","position":9,"is_corresponding":false},{"id":393555,"name":"Luda Diatchenko","orcid":"0000-0002-1350-6727","position":10,"is_corresponding":false},{"id":1082466,"name":"Audrey V. Grant","orcid":"0000-0002-4197-0818","position":11,"is_corresponding":false},{"id":1478919,"name":"Goodarz Koli Farhood","orcid":null,"position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:57:23.653298Z","pmid":"40832418","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}