Associations between coeliac disease and musculoskeletal conditions: epidemiology and genetic evidence from a large-scale cohort study.

OBJECTIVES: Coeliac disease (CeD) is an autoimmune enteropathy triggered by gluten exposure and is often accompanied by musculoskeletal (MSK) manifestations, but evidence on their overall comorbidity patterns remains limited. METHODS: Using UK Biobank data, we conducted prospective cohort and cross-sectional analyses to systematically evaluate associations between CeD and 24 MSK conditions. Cox proportional hazards models were used to estimate associations, and logistic regression was applied to assess graded cross-sectional association between MSK burden and CeD odds. Effect modification by polygenic risk score (PRS) was also examined. To further characterize shared genetic architecture and potential directional genetic evidence, linkage disequilibrium score regression (LDSC) and generalized summary-data-based Mendelian randomization (GSMR) were performed using external GWAS summary statistics. RESULTS: In the cohort analyses, 6 MSK conditions-osteoporosis, osteoarthritis, rheumatoid arthritis, systemic lupus erythematosus, spondylosis, and enthesopathies/synovial disorders-were significantly associated with CeD after FDR correction. Greater overall MSK burden was also associated with CeD in both directions (CeD as exposure: HR = 1.68, 95% CI 1.51-1.87; CeD as outcome: HR = 2.31, 95% CI 2.12-2.51). Higher PRS and increasing MSK burden independently increased CeD odds. LDSC identified FDR-significant positive genetic correlations of CeD with osteoporosis (rg = 0.307) and rheumatoid arthritis (rg = 0.279), whereas no consistent genetic correlation was observed for enthesopathies/synovial disorders. Exploratory GSMR identified several FDR-significant directional genetic associations involving osteoporosis, rheumatoid arthritis, and lupus erythematosus. CONCLUSIONS: These findings demonstrate consistent epidemiological associations between CeD and several MSK conditions and suggest partially shared genetic architecture. The results support greater clinical awareness of CeD-MSK co-occurrence but do not establish causality or a screening strategy. Key Points • This study systematically evaluated the bidirectional associations between coeliac disease and 24 musculoskeletal conditions in a large-scale population-based cohort. • Coeliac disease was associated with the subsequent occurrence of six musculoskeletal conditions, and greater musculoskeletal burden was associated with prevalent coeliac disease. • Higher polygenic risk score and greater musculoskeletal burden were jointly associated with higher odds of prevalent coeliac disease; however, the interaction test was not statistically significant. • Genetic analyses suggested shared genetic architecture, particularly for osteoporosis and rheumatoid arthritis, while directional GSMR findings require cautious interpretation.