Fig. 1

Diagrams illustrating associations examined in this study. A The total effect of exposure on outcome, c, was derived using univariable MR. B The total effect was decomposed into: (i) indirect effect using a two-step MR (where a is the total effect of exposure on mediator, b is the effect of mediator on outcome adjusting for exposure and the mediating effect is calculated using the product method (a × b)); (ii) direct effect (c' = c – a × b). C For mediation by both smoking and BMI combined (arrows represent their bidirectional causal relationship), the indirect effect was derived using the difference method (c–c'). Proportion mediated was the indirect effect divided by the total effect