Statistical Analysis and Multiple Testing Correction

Analyses were conducted using the “sqldf,” “biomaRt,” “TwoSampleMR,” “MendelianRandomization,” or “simex” modules in the R package (version 4.0.3). In general, statistical significance was defined as p < 0.05. In the case of multiple testing, the threshold for statistical significance was adjusted by the conservative Bonferroni correction according to the formula p < 0.05/n, where n referred to the number of MR tests. Since the present study included five forward and one reverse two-sample MR analyses, the adjusted p-values for the forward and reverse MR tests were, respectively, 0.01 (0.05/5) and 0.05 (0.05/1). When a p-value for an association was below the adjusted cut-off value, the association was considered statistically significant as a causal association. When a p-value was below 0.05 but equal to or greater than the adjusted cut-off value, the association was considered one of potential causality needing further confirmation. When a p-value was equal to or >0.05, it was considered not to be causal.