two-fold increased risk of schizophrenia in smokers compared with non-smokers (Scott et al., 2018). Some studies which adjust for potential confounders find the effect of smoking attenuates to the null (Jones et al., 2018) or even becomes protective (Zammit et al., 2003), demonstrating that there are likely to be substantial confounding effects in observational studies. Previous MR studies have not found clear evidence to support smoking as a risk factor for either schizophrenia or depression (Bjørngaard et al., 2013; Gage et al., 2017; Taylor, Fluharty et al., 2014; Wium-Andersen et al., 2015), but our approach offers greater power, captures multiple aspects of smoking behaviour and enables two-sample MR analysis using summary data in unstratified samples. However, it is not possible to precisely estimate from our results what proportion of the observational association between smoking, schizophrenia and depression is causal, or the population attributional fraction of these disorders due to smoking.
