Target Discovery for Drug Development Using Mendelian Randomization

Making drug development more efficient by identifying promising drug targets can contribute to resource savings. Identifying promising drug targets using human genetic approaches can remove barriers related to translation. In addition, genetic information can be used to identify potentially causal relationships between a drug target and disease. Mendelian randomization (MR) is a class of approaches used to identify causal associations between pairs of genetically predicted traits using data from human genetic studies. MR can be used to prioritize candidate drug targets by predicting disease outcomes and adverse events that could result from the manipulation of a drug target. The theory behind MR is reviewed, including a discussion of MR assumptions, different MR analytical methods, tests for violations of assumptions, and MR methods that can be robust to some violations of MR assumptions. A protocol to perform two-sample MR (2SMR) with summary genome-wide association study (GWAS) results is described. An example of 2SMR examining the causal relationship between low-density lipoprotein (LDL) and coronary artery disease (CAD) is provided as an illustration of the protocol.