Genetic axes of hand and shoulder soft-tissue disease and their divergent responses to adiposity and incretin therapy: a cross-biobank genomic and randomised trial study

Background: Hand and shoulder soft-tissue disorders cluster in people with obesity and diabetes, now widely treated with incretin receptor agonists. Whether these disorders share genetic causes, and whether pharmacological weight loss relieves or provokes them, is unknown. Methods: We analysed genome-wide data on seven disorders from FinnGen and UK Biobank (over 900,000 participants) by genomic structural equation modelling, tested five endocrine and metabolic exposures by Mendelian randomisation, mapped heritability onto 110,020 connective-tissue cells, and pooled serious adverse events from 210 placebo-controlled trials of incretin receptor agonists (134,138 participants). Findings: The disorders formed two replicated heritable axes: tenosynovial (carpal tunnel syndrome, trigger finger, de Quervain tenosynovitis; 61 loci) and fibro-capsular (frozen shoulder, Dupuytren's disease, plantar fascial disorder; 42 loci). Each SD higher genetically predicted body mass index increased the odds of carpal tunnel syndrome (odds ratio [OR] 1.67, 95% CI 1.47-1.89; P = 6.9 x 10^-16) and decreased those of Dupuytren's disease (0.57, 0.46-0.71; P = 8.7 x 10^-7), whose heritability concentrated in lesional POSTN+ fibroblasts. Incretin receptor agonists increased serious fibro-capsular events (Peto OR 3.88, 1.83-8.25; P = 4.1 x 10^-4), including frozen shoulder (4.16, 1.50-11.54) and Dupuytren's disease (3.58, 1.17-10.93), but not tenosynovial events (1.02, 0.60-1.75). Interpretation: Hand and shoulder soft-tissue disease comprises two genetically distinct axes with opposite responses to adiposity. It identifies frozen shoulder and Dupuytren's disease as musculoskeletal pharmacovigilance targets for the millions receiving incretin receptor agonists. Funding: Health Commission of Hubei Province (WJ2023F086) and Department of Science and Technology of Hubei Province (2024BCB059).