Our study is the first to generate a genetic instrument for lifetime smoking behaviour in a large sample, which allows the use of two-sample MR with summary data from unstratified samples to answer questions about the association between smoking and other health outcomes. However, there are some limitations which should be noted. First, there is evidence to suggest that even after seemingly controlling for population structure in GWAS of samples as large as the UK Biobank, coincident apparent structure remains (Haworth et al., 2019). This might confound the association between smoking and mental health, increasing the risk of false positives. As independent samples with adequate sample size become available, the influence of structure should be further explored. However, it is reassuring that our instrument predicted lifetime smoking in an independent replication sample, where such issues would not arise in the same manner.
