We conducted a GWAS of lifetime smoking exposure which provides a novel genetic instrument that can be used in two-sample MR of summary data without the need to stratify on smoking status. We used this novel genetic instrument along with a new instrument of smoking initiation to explore possible causal pathways between smoking, schizophrenia and depression. The two-sample MR results provide strong evidence that smoking is a risk factor for both schizophrenia and depression. This supports prospective observational evidence controlling for genetic confounding (Kendler et al., 1993, 2015), as well as meta-analyses of observational studies (Gurillo et al., 2015; Taylor, McNeill et al., 2014) (although it should be noted that these meta-analyses include estimates not adjusted for known confounders e.g. cannabis use). Effect sizes were similar to a more recent meta-analysis that did adjust for multiple confounders and found a 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
