Directionality test.

To exclude MR signals caused by reverse causality (i.e., methylation changes caused by outcome phenotype), we applied MR Steiger test ²¹, which is the method to test the directionality of causal effect estimated by MR. We then removed all MR signals with reverse directionality. We also applied the cis-reverse MR on the CpG-outcome pairs if the genome-wide significant instrument for the outcome traits is available. The CpG-outcome pairs with correct causal effect direction and non-significant reverse causal effects are marked as with correct causal direction.