AbstractBackgroundThe potential of Mendelian Randomization studies is rapidly expanding due to (i) the growing power of GWAS meta-analyses to detect genetic variants associated with several exposures, and (ii) the increasing availability of these genetic variants in large-scale surveys. However, without a proper biological understanding of the pleiotropic working of genetic variants, a fundamental assumption of Mendelian Randomization (the exclusion restriction) can always be contested.MethodsWe build upon and synthesize recent advances in the econometric literature on instrumental variables (IV) estimation that test and relax the exclusion restriction. Our Pleiotropy-robust Mendelian Randomization (PRMR) method first estimates the degree of pleiotropy, and in turn corrects for it. If a sample exists for which the genetic variants do not affect the exposure, and pleiotropic effects are homogenous, PRMR obtains unbiased estimates of causal effects in case of pleiotropy.ResultsSimulations show that existing MR methods produce biased estimators for realistic forms of pleiotropy. Under the aforementioned assumptions, PRMR produces unbiased estimators. We illustrate the practical use of PRMR by estimating the causal effect of (i) cigarettes smoked per day on Body Mass Index (BMI); (ii) prostate cancer on self-reported health, and (iii) educational attainment on BMI in the UK Biobank data.ConclusionsPRMR allows for instrumental variables that violate the exclusion restriction due to pleiotropy, and corrects for pleiotropy in the estimation of the causal effect. If the degree of pleiotropy is unknown, PRMR can still be used as a sensitivity analysis.Key messagesIf genetic variants have pleiotropic effects, causal estimates of Mendelian Randomization studies will be biased.Pleiotropy-robust Mendelian Randomization (PRMR) produces unbiased causal estimates in case (i) a subsample can be identified for which the genetic variants do not affect the exposure, and (ii) pleiotropic effects are homogenous.If such a subsample does not exist, PRMR can still routinely be reported as a sensitivity analysis in any MR analysis.If pleiotropic effects are not homogenous, PRMR can be used as an informal test to gauge the exclusion restriction.