A Novel Method for Mendelian Randomization Analyses With Pleiotropy and Linkage Disequilibrium in Genetic Variants From Individual Data

Mendelian randomization makes use of genetic variants as instrumental variables to eliminate the influence induced by unknown confounders on causal estimation in epidemiology studies. However, with the soaring genetic variants identified in genome-wide association studies, the pleiotropy, and linkage disequilibrium in genetic variants are unavoidable and may produce severe bias in causal inference. In this study, by modeling the pleiotropic effect as a normally distributed random effect, we propose a novel mixed-effects regression model-based method PLDMR, pleiotropy and linkage disequilibrium adaptive Mendelian randomization, which takes linkage disequilibrium into account and also corrects for the pleiotropic effect in causal effect estimation and statistical inference. We conduct voluminous simulation studies to evaluate the performance of the proposed and existing methods. Simulation results illustrate the validity and advantage of the novel method, especially in the case of linkage disequilibrium and directional pleiotropic effects, compared with other methods. In addition, by applying this novel method to the data on Atherosclerosis Risk in Communications Study, we conclude that body mass index has a significant causal effect on and thus might be a potential risk factor of systolic blood pressure. The novel method is implemented in R and the corresponding R code is provided for free download.

Automated summary

Mendelian randomization is a powerful tool in epidemiology studies, but the increasing number of genetic variants may lead to bias in causal inference. The proposed PLDMR method takes into account pleiotropy and linkage disequilibrium, correcting for these effects and demonstrating advantages in simulation studies. The novel method was applied to Atherosclerosis Risk in Communications Study data, showing a significant causal effect of body mass index on systolic blood pressure and providing a free downloadable R code for implementation.