Genetic evidence elucidates the mediating role of sex hormone-binding globulin in the causal relationship linking insomnia to carpal tunnel syndrome

BACKGROUND: Carpal tunnel syndrome (CTS) is the most prevalent type of entrapment neuropathy and is frequently associated with sleep disturbances. However, the directionality of this association remains ambiguous, necessitating an exploration of potential mediators. Sex hormone-binding globulin (SHBG) may affect the risk of CTS by modulating the sex hormone milieu within the carpal tunnel. This study seeks to elucidate the causal relationship between sleep disturbances and CTS and to assess the mediating role of SHBG. METHOD: Comprehensive summary-level data on sleep traits and CTS from Genome-wide association studies (GWAS) were gathered in this study. The causal analysis between sleep traits and CTS was carried out using two-sample MR. Additionally, two-step MR analysis was employed to study the mediating effect of SHBG on the causal relationship between sleep traits and CTS. RESULTS: We examined the genetic causal relationships between nine sleep traits and CTS. Only insomnia genetically predicted the increased risk of CTS. The backward MR analyses showed no causal associations of CTS with any sleep traits. Exploratory mediation analysis suggested that SHBG may represent a putative partial explanatory pathway between insomnia and CTS, accounting for approximately 2.1% of the total association. CONCLUSION: This genetic evidence demonstrates that insomnia is an independent risk factor for CTS, with SHBG acting as a putative hormonal mediator or genetically correlated pathway in this relationship. The findings highlight sleep management as a potential preventive strategy for CTS and warrant mechanistic and clinical validation.