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

Rotator cuff tendinopathy (RCT) is a major contributor to over 30 million surgeries which are conducted to treat shoulder overuse injuries worldwide annually. Accumulating evidence indicates that neuropsychiatric disorders (ND) share pathogenic pathways with tendinopathy. However, unclarified causal relationships between these two disease spectra undermine the individualized design of treatment strategies benefiting patients with ND while minimizing the RCT risk. We aimed to unveil whether ND were genetically associated with increased RCT occurrence by conducting a two-sample Mendelian randomization (MR) algorithm.

Genome-wide association studies (GWAS) data of attention deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), epilepsy, major depressive disorder (MDD), obsessive compulsive disorder (OCD), post-traumatic stress disorder (PTSD), schizophrenia (SCZ), and RCT patients of European ancestry were retrieved for bidirectional two-sample Mendelian randomization (MR) analyses to establish causal relationships among these 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 tests. Body shape, lifestyle, and socioeconomic parameters were adjusted as mediators in multivariable MR to validate the robustness of the results.

Univariable MR revealed that genetic predisposition to ADHD (odds ratio [OR] 1.14, 95% confidence interval [CI] 1.05-1.24, p = 0.001) and PTSD (OR 2.23, 95% CI 1.75-2.84, p < 0.001) significantly increased the RCT risk. MDD showed a similar association (OR 1.21, 95% CI 1.06-1.38, p = 0.004), which was attenuated after confounder adjustment (p = 0.78). Multivariable MR confirmed ADHD (OR 1.09, 95% CI 1.01-1.18, p = 0.02) and PTSD (OR 2.00, 95% CI 1.41-2.82, p < 0.001) as robust causal factors for RCT after adjusting for anthropometric, lifestyle, physical activity, and socioeconomic confounders.

Our study sheds new light on the need for early screening, targeted overuse injury prevention, and specialized clinical interventions to alleviate the RCT burden in ADHD and PTSD populations.