The use of two-sample methods for Mendelian randomization analyses on single large datasets

Abstract

BackgroundWith genome-wide association data for many exposures and outcomes now available from large biobanks, one-sample Mendelian randomization (MR) is increasingly used to investigate causal relationships. Many robust MR methods are available to address pleiotropy, but these assume independence between the gene-exposure and gene-outcome association estimates. Unlike in two-sample MR, in one-sample MR the two estimates are obtained from the same individuals, and the assumption of independence does not hold in the presence of confounding. MethodsWith simulations mimicking a typical study in UK Biobank we assessed the performance, in terms of bias and precision of the MR estimate, of the fixed-effect and (multiplicative) random-effects meta-analysis method, weighted median estimator, weighted mode estimator and MR-Egger regression, used in both one-sample and two-sample data. We considered scenarios differing for: presence/absence of a true causal effect; amount of confounding; presence and type of pleiotropy (none, balanced or directional). ResultsEven in the presence of substantial correlation due to confounding, all methods performed well when used in one-sample MR except for MR-Egger, which resulted in bias reflecting direction and magnitude of the confounding. Such bias was much reduced in the presence of very high variability in instrumental strength across variants (I2GX of 97%). ConclusionsTwo-sample MR methods can be safely used for one-sample MR performed within large biobanks, expect for MR-Egger. MR-Egger is not recommended for one-sample MR unless the correlation between the gene-exposure and gene-outcome estimates due to confounding can be kept low, or the variability in instrumental strength is very high. Key MessagesO_LICurrent availability of phenotypic and genetic data from large biobanks, such as UK Biobank, has led to increasing use of one-sample Mendelian randomization (MR) to investigate causal relationships in epidemiological research C_LIO_LIRobust MR methods have been developed to address pleiotropy, but they assume independence between the gene-exposure and gene-outcome association estimates; this holds in two-sample MR but not in one-sample MR C_LIO_LIWe illustrate the practical implications, in terms of bias and precision of the MR causal effect estimate, of using robust two-sample methods in one-sample MR studies performed within large biobanks C_LIO_LITwo-sample MR methods can be safely used for one-sample MR performed within large biobanks, expect for MR-Egger regression C_LIO_LIMR-Egger is not recommended for one-sample MR unless the correlation between the gene-exposure and gene-outcome estimates due to confounding can be kept low, or the variability in instrumental strength is very high C_LI