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 different methods for schizophrenia on smoking initiation (IVW: β = 0.010, 95% CI 0.000–0.021, p = 0.04) (see Table 2). Overall, the effect was larger and more consistent for depression than for schizophrenia. We saw similar effects using the more recent meta-analysed GWAS for schizophrenia with an additional 11 260 cases (see online Supplementary Table S9). There was evidence of significant heterogeneity (see online Supplementary Table S4) but MR Egger intercepts suggest directional pleiotropy is not biasing the estimates (see online Supplementary Table S5) and Steiger filtering supported the conclusion that the effects operate in both directions (see online Supplementary Table S6). Given that variants from the CHRNA5-A3-B4 gene complex were identified in both GWAS of lifetime smoking and schizophrenia, we conducted a sensitivity analysis removing these variants and the effects remained consistent (see online Supplementary Table S10). Table 1.Two-sample MR analyses of the effect of smoking exposure on schizophrenia and depressionExposureOutcomeMethodN SNPOR (95% CI)p valueLifetime smokingSchizophreniaInverse-variance weighted1252.27 (1.67–3.08)1.36 ×
