| Summary: | Abstract Background The causal relationship between work‐related factors and amyotrophic lateral sclerosis (ALS) is unclear. We used a Mendelian randomization (MR) analysis to investigate the unconfounded association between work‐related factors and ALS. Methods Univariable MR analyses were conducted to evaluate the causal effects of work‐related factors on ALS. Instrumental variables from the UK Biobank on work‐related factors (n = 263,615) were used as proxies. The outcome dataset used ALS (n case = 20,806, n control = 59,804) summary‐level data from a large‐scale genome‐wide association study based on European ancestry. MR analysis used inverse variance weighted (IVW), MR‐Egger, and weighted median (WM) to assess causal effects and other methods of MR for sensitivity analysis. Further multivariable MR analyses were performed to explore potential mediating effects. Results In univariable MR, IVW methods support evidence that genetically determined job involves heavy manual or physical work (OR = 2.04, 95% CI: 1.26–3.31; p = .004) was associated with an increased risk of ALS, and the WM methods also confirm this result (OR = 2.36, 95% CI: 1.30–4.28; p = .005). No evidence of heterogeneity or horizontal pleiotropy was found in the results. In multivariable MR, the association was absent after adjusting for smoking and blood pressure. Conclusions Our MR analysis results demonstrate the potential causal relationship between jobs that involve heavy manual or physical work and ALS, which might be mediated by smoking and high systolic blood pressure.
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