Selecting likely causal risk factors from high-throughput experiments using multivariable Mendelian randomization

Nat Commun. 2020 Jan 7;11(1):29. doi: 10.1038/s41467-019-13870-3.

Abstract

Modern high-throughput experiments provide a rich resource to investigate causal determinants of disease risk. Mendelian randomization (MR) is the use of genetic variants as instrumental variables to infer the causal effect of a specific risk factor on an outcome. Multivariable MR is an extension of the standard MR framework to consider multiple potential risk factors in a single model. However, current implementations of multivariable MR use standard linear regression and hence perform poorly with many risk factors. Here, we propose a two-sample multivariable MR approach based on Bayesian model averaging (MR-BMA) that scales to high-throughput experiments. In a realistic simulation study, we show that MR-BMA can detect true causal risk factors even when the candidate risk factors are highly correlated. We illustrate MR-BMA by analysing publicly-available summarized data on metabolites to prioritise likely causal biomarkers for age-related macular degeneration.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bayes Theorem
  • Genome-Wide Association Study
  • Humans
  • Mendelian Randomization Analysis / methods*
  • Models, Genetic*
  • Risk Factors