Smoking has been widely studied as a susceptibility factor for ALS, but results are conflicting. This study used the results of recently published large genome-wide association studies and Mendelian randomisation methods to reduce confounding to assess the relationship between smoking and ALS.

Two genome-wide association studies investigating lifetime smoking in 463 003 participants and ever smoking in 1 232 091 participants, were identified and used to define instrumental variables for smoking. A genome-wide association study of ALS in 20 806 cases using 59 804 controls to see the outcome for inverse variance weighted Mendelian randomisation, and four other Mendelian randomisation methods, to test whether smoking is causal for ALS. Analyses were bidirectional to assess reverse causality.

There was no strong evidence for a causal or reverse causal relationship between smoking and ALS. The results of Mendelian randomisation using the inverse variance weighted method were: lifetime smoking OR 0.94 (95% CI 0.74 to 1.19), p value 0.59; ever smoking OR 1.10 (95% CI 1 to 1.23), p value 0.05.

The study concluded that there is no evidence with Mendelian randomisation techniques that smoking causes ALS even after using multiple methods, large sample sizes and sensitivity analyses.