In order to evaluate whether the limitations of MR observed in simulations (Figure 2) are also observed in analyses of real traits, we applied MR, MR-Egger and Bidirectional MR to all 429 genetically correlated trait pairs (Supplementary Table 12). MR reported significant causal relationships (1% FDR) for 271/429 trait pairs, including 155 pairs of traits for which each trait was reported to be causal for the other trait. This implausible result confirms that MR frequently produces false positives in the presence of a genetic correlation, as predicted by our simulations (Figure 2). In contrast, LCV reported a significant partially or fully genetically causal relationship for only 59 trait pairs (Supplementary Table 11), and it never reports a causal effect in both directions. Similarly, Bidirectional MR reported a significant causal relationship for only 45 trait pairs (including 17 pairs of traits that overlapped with LCV; Supplementary Table 15).
