Decoding Causal Associations Between Neuropsychiatric Disorders and Rotator Cuff Tendinopathy: A Two-Sample Mendelian Randomization Study

Background/Objectives: Rotator cuff tendinopathy (RCT) contributes to over 30 million sports-related surgeries worldwide annually, as a leading cause of shoulder pain and dysfunction. Emerging evidence indicates that neuropsychiatric disorders (ND) may share overlapping etiology with tendinopathic conditions. However, no research estimates the causal relationships between ND and RCT due to inherent biases derived from confounders and reverse causation of traditional observational studies. Methods: Two-sample univariable and multivariable Mendelian Randomization (MR) analyses were applied using summary data from genome-wide association studies (GWAS) to establish causal relationships among eight main types of ND and RCT. To detect false positive findings, MR-Egger, weighted median and causal analysis using summary effect estimates (CAUSE) were employed as sensitivity test sensitivity. Body shape, lifestyle, and socioeconomic parameters were adjusted as mediators in multivariable MR to validate the robustness of the results. Results: Univariable MR revealed that genetic predisposition to attention deficit/hyperactivity disorder (ADHD) (odds ratio [OR] 1.14, 95% confidence interval [CI] 1.05–1.24, p = 0.001) and post-traumatic stress disorder (PTSD) (OR 2.23, 95% CI 1.75–2.84, p < 0.001) significantly increased the RCT risk. Major depressive disorder (MDD) showed a similar association (OR 1.21, 95% CI 1.06–1.38, p = 0.004), which was attenuated after confounder adjustment (p = 0.783). Multivariable MR confirmed ADHD (OR 1.09, 95% CI 1.01–1.18, p = 0.024) and PTSD (OR 2.00, 95% CI 1.41–2.82, p < 0.001) as robust causal factors for RCT after adjusting for the confounders. Conclusions: Our study identified ADHD and PTSD as independent genetic risk factors for RCT. These findings shed new lights on the importance of early targeted prevention and integrated clinical interventions to alleviate the RCT burden in ADHD and PTSD populations.