Hyperglycemia is a causal risk factor for upper limb pathologies

This is the final version. Available on open access from Oxford University Press via the DOI in this record ; Data Availability: All individual level data used in this paper was obtained from the UK Biobank resource, and can be obtained from the UK Biobank at https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access. Information on recruitment, locations and data collection methods can be found in 11. Access to summary statistics from the FinnGen resource can be obtained at https://www.finngen.fi/en/access_results/. ; Background: Diabetes (regardless of type) and obesity are associated with a range of musculoskeletal disorders. The causal mechanisms driving these associations are unknown for many upper limb pathologies. We used genetic techniques to test the causal link between glycemia, obesity, and musculoskeletal conditions. Methods: In the UK Biobank’s unrelated European cohort (N=379,708) we performed Mendelian Randomisation (MR) analyses to test for a causal effect of long-term high glycaemia and adiposity on four musculoskeletal pathologies: frozen shoulder, Dupuytren’s disease, carpal tunnel syndrome and trigger finger. We also performed single-gene MR using rare variants in the GCK gene. Results: Using MR, we found evidence that long-term high glycaemia has a causal role in the aetiology of upper limb conditions. A 10 mmol/mol increase in genetically predicted haemoglobin A1C (HbA1c) was associated with frozen shoulder: odds ratio (OR)=1.50 (95% confidence interval (CI) 1.20-1.88), Dupuytren’s disease: OR=1.17 (95% CI 1.01-1.35), trigger finger: OR=1.30 (95% CI 1.09-1.55) and carpal tunnel syndrome: OR=1.20 (95% CI 1.09-1.33). Carriers of GCK mutations have increased odds of frozen shoulder: OR=7.16 (95% CI 2.93-17.51) and carpal tunnel syndrome: OR=2.86 (95% CI 1.50-5.44) but not Dupuytren’s disease or trigger finger. We found evidence that an increase in genetically predicted body mass index (BMI) of 5 kg/m^2 was associated with carpal tunnel syndrome: OR=1.13 (95% CI 1.10-1.16) and associated ...