MR analyses were run using the MR Base R package (Hemani et al., 2018; R. Core Team, 2014) and compared across five different methods: inverse-variance weighted, MR Egger (Bowden, Davey Smith, & Burgess, 2015), weighted median (Bowden, Davey Smith, Haycock, & Burgess, 2016), weighted mode (Hartwig, Smith, & Bowden, 2017) and MR RAPS (Zhao, Wang, Hemani, Bowden, & Small, 2018). Each of these methods makes slightly different assumptions about the nature of pleiotropy and therefore a roughly consistent point estimate across the multiple methods provides the strongest evidence of causal inference (Lawlor, Tilling, & Davey Smith, 2016), with the Inverse variance weighted (IVW) method being the main analysis and each other method providing a sensitivity analysis. For additional details on each of the methods see online Supplementary Table S12. Two-sample MR analysis was run bi-directionally, first with smoking as the exposure and then as the outcome. To test the suitability of the MR Egger method, the I2GX statistic was calculated to quantify the degree of regression dilution bias due to measurement error of SNP-exposure effects (Bowden et al., 2016). We
