Genetic predisposition to smoking and the risk of Carpal Tunnel Syndrome: a mendelian randomization study

• Genetics establishes smoking as a cause of Carpal Tunnel Syndrome. • Genetic predisposition to smoking raises the risk of Carpal Tunnel Syndrome. • Finding is robust to genetic confounding. • Quitting smoking is key to preventing Carpal Tunnel Syndrome. Carpal Tunnel Syndrome (CTS) is a common entrapment neuropathy leading to pain and functional impairment. While smoking has been proposed as a modifiable risk factor, evidence from observational studies remains inconsistent due to potential confounding and reverse causality. The authors performed a two-sample Mendelian Randomization (MR) analysis to assess the causal relationship. Genetic instruments for five smoking phenotypes were derived from large-scale Genome-Wide Association Studies (GWAS). Summary-level data for CTS were obtained from the FinnGen Consortium (n = 480,201). The Inverse Variance Weighted (IVW) method was the primary analysis, supplemented by four other MR methods and a suite of sensitivity analyses to assess robustness and pleiotropy. Genetically predicted smoking propensity was associated with a higher risk of CTS. Specifically, genetic predisposition to smoking initiation (ORMR-IVW = 1.53; 95% CI 1.33–1.76; p < 0.001) and heavier cigarette consumption (ORMR-IVW = 1.52; 95% CI: 1.31–1.77; p < 0.001) significantly increased CTS risk. The estimate for current smoking was particularly strong (ORMR-IVW=3.96; 95% CI 2.20–7.12; p < 0.001). Sensitivity analyses were largely consistent, though some heterogeneity and potential pleiotropy were detected for specific phenotypes. This MR study supports a causal role of smoking in the development of CTS. These findings underscore the importance of smoking cessation as a potential preventive measure against CTS and should be integrated into patient counseling and public health strategies.