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

Genetically distinct hand and shoulder soft-tissue disorders split into two heritable axes—tenosynovial (61 loci) and fibro-capsular (42 loci)—with opposite adiposity-linked odds.

• Why it matters: Obesity and diabetes cluster these conditions and incretin receptor agonists are widely used, but shared genetic causes and whether weight-loss therapy changes risk were unknown.
• What they did: Using genome-wide data from FinnGen and UK Biobank (>900,000 participants), the study used genomic structural equation modelling and Mendelian randomisation, plus cell heritability mapping to 110,020 connective-tissue cells. It pooled serious adverse events from 210 placebo-controlled incretin receptor agonist trials (134,138 participants).
• The result: Each genetically higher BMI increased carpal tunnel syndrome odds (OR 1.67, 95% CI 1.47–1.89; P = 6.9 x 10^-16) but decreased Dupuytren’s disease odds (0.57, 0.46–0.71; P = 8.7 x 10^-7), while 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).