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Methodological Challenges in Mendelian Randomization

VanderWeele, Tyler J.a; Tchetgen Tchetgen, Eric J.a; Cornelis, Marilynb; Kraft, Petera

doi: 10.1097/EDE.0000000000000081

We give critical attention to the assumptions underlying Mendelian randomization analysis and their biological plausibility. Several scenarios violating the Mendelian randomization assumptions are described, including settings with inadequate phenotype definition, the setting of time-varying exposures, the presence of gene–environment interaction, the existence of measurement error, the possibility of reverse causation, and the presence of linkage disequilibrium. Data analysis examples are given, illustrating that the inappropriate use of instrumental variable techniques when the Mendelian randomization assumptions are violated can lead to biases of enormous magnitude. To help address some of the strong assumptions being made, three possible approaches are suggested. First, the original proposal of Katan (Lancet. 1986;1:507–508) for Mendelian randomization was not to use instrumental variable techniques to obtain estimates but merely to examine genotype–outcome associations to test for the presence of an effect of the exposure on the outcome. We show that this more modest goal and approach can circumvent many, though not all, the potential biases described. Second, we discuss the use of sensitivity analysis in evaluating the consequences of violations in the assumptions and in attempting to correct for those violations. Third, we suggest that a focus on negative, rather than positive, Mendelian randomization results may turn out to be more reliable.

From the aDepartments of Epidemiology and Biostatistics, Harvard School of Public Health, Boston, MA; and bDepartment of Nutrition, Harvard School of Public Health, Boston, MA.

T.J.V.W was supported by National Institutes of Health grant ES017876. E.J.T.T. was supported by National Institutes of Health grants R01AI104459 and R01ES020337.

Correspondence: Tyler J. VanderWeele, Harvard School of Public Health, Departments of Epidemiology and Biostatistics, 677 Huntington Ave., Boston, MA 02115. E-mail:

© 2014 by Lippincott Williams & Wilkins, Inc