Invited Commentary: Detecting Individual and Global Horizontal Pleiotropy in Mendelian Randomization—A Job for the Humble Heterogeneity Statistic?

Mendelian randomization (MR) is gaining in recognition and popularity as a method for strengthening causal inference in epidemiology by utilizing genetic variants as instrumental variables. Concurrently with the explosion in empirical MR studies, there has been the steady production of new approaches for MR analysis. The recently proposed “global and individual tests for direct effects” (GLIDE) approach fits into a family of methods that aim to detect horizontal pleiotropy—at the individual single nucleotide polymorphism level and at the global level—and to adjust the analysis by removing outlying single nucleotide polymorphisms. In this commentary, we explain how existing methods can (and indeed are) being used to detect pleiotropy at the individual and global levels, although not explicitly using this terminology. By doing so, we show that the true comparator for GLIDE is not MR-Egger regression (as Dai et al., the authors of the accompanying article (Am J Epidemiol. 2018;187(12):2672–2680), claim) but rather the humble heterogeneity statistic.