Bi-directional MR analyses provided strong evidence that higher lifetime smoking increases risk of both schizophrenia [IVW: odds ratio (OR) 2.27, 95% confidence interval (CI) 1.67–3.08, p < 0.001] and depression (IVW: OR 1.99, 95% CI 1.71–2.32, p < 0.001) (see Table 1), with consistent direction of effect across all five MR methods. The same was seen for smoking initiation as the instrument on schizophrenia (IVW: OR 1.53, 95% CI 1.35–1.74, p < 0.001) and depression (IVW: OR 1.54, 95% CI 1.44–1.64, p < 0.001) (see Table 1). MR Egger results are the least reliable due to low I2GX (see online Supplementary Table S3). There was also evidence of a consistent but smaller effect of higher genetic liability for schizophrenia on lifetime smoking (IVW: β = 0.022, 95% CI 0.005–0.038, p = 0.009) and of genetic liability for depression on lifetime smoking (IVW: β = 0.091, 95% CI 0.027–0.155, p = 0.005) (see Table 2). These effects remained for depression on smoking initiation (IVW: β = 0.083, 95% CI 0.039–0.127, p < 0.001) but became even weaker and inconsistent across the
