Genome-Wide Association Study of Adhesive Capsulitis Suggests Significant Genetic Risk Factors

Background: Adhesive capsulitis of the shoulder involves loss of passive range of motion with associated pain and can develop spontaneously, with no obvious injury or inciting event. The pathomechanism of this disorder remains to be elucidated, but known risk factors for adhesive capsulitis include diabetes, female sex, and thyroid dysfunction. Additionally, transcriptional profiling and pedigree analyses have suggested a role for genetics. Identification of elements of genetic risk for adhesive capsulitis using population-based techniques can provide the basis for guiding both the personalized treatment of patients based on their genetic profiles and the development of new treatments by identification of the pathomechanism. Methods: A genome-wide association study (GWAS) was conducted using the U.K. Biobank (a collection of approximately 500,000 patients with genetic data and associated ICD-10 [International Classification of Diseases, 10th Revision] codes), comparing 2,142 patients with the ICD-10 code for adhesive capsulitis (M750) to those without. Separate GWASs were conducted controlling for 2 of the known risk factors of adhesive capsulitis-hypothyroidism and diabetes. Logistic regression analysis was conducted controlling for factors including sex, thyroid dysfunction, diabetes, shoulder dislocation, smoking, and genetics. Results: Three loci of significance were identified: rs34315830 (in WNT7B; odds ratio [OR] = 1.28; 95% confidence interval [CI], 1.22 to 1.39), rs2965196 (in MAU2; OR = 1.67; 95% CI, 1.39 to 2.00), and rs1912256 (in POU1F1; OR = 1.22; 95% CI, 1.14 to 1.31). These loci retained significance when controlling for thyroid dysfunction and diabetes. The OR for total genetic risk was 5.81 (95% CI, 4.08 to 8.31), compared with 1.70 (95% CI, 1.18 to 2.36) for hypothyroidism and 4.23 (95% CI, 2.32 to 7.05) for diabetes. Conclusions: The total genetic risk associated with adhesive capsulitis was significant and similar to the risks associated with hypothyroidism and diabetes. Identification of WNT7B, POU1F1, and MAU2 implicates the Wnt pathway and cell proliferation response in the pathomechanism of adhesive capsulitis.