no evidence of heterogeneity in the MD-AD result (P > 0.13; online Supplemental Table S3). The MR-PRESSO global test (Verbanck et al., 2018) also supported the absence of horizontal pleiotropy (RSSobs = 285.6, P = 0.143). The MR-RAPS overdispersion test did not observe significant horizontal pleiotropy (estimated pleiotropy variance = 1 × 10−4; P = 0.249). Finally, the funnel plot and leave-one-out analyses provided additional support that the MD-AD result was not biased by outliers included in the genetic instrument (online Supplemental Figure S2). The same MD genetic instrument also showed significant effects on AC-quantity and AC-frequency (Table 1), but, in contrast to the AD outcome, these causal effects showed evidence of non-consistency across MR methods, heterogeneity, and horizontal pleiotropy (online Supplemental Table S3, S5, S6). No reverse causal effect was observed between AD genetic instrument and MD (fixed-effect inverse-variance weighted method: β = 0.01, P = 0.1), which also showed non-concordant direction of effects across MR methods (online Supplemental Figure S3). Conversely, the AD genetic instrument showed significant effects on AC-quantity and AC-frequency but was affected by heterogeneity and horizontal pleiotropy (Table 1; online Supplemental Table S3, S6).
