Abstract
Drugs whose targets have genetic evidence to support efficacy and safety are more likely to be approved after clinical development. In this paper, we provide an overview of how natural sequence variation in the genes that encode drug targets can be used in Mendelian randomization analyses to offer insight into mechanism-based efficacy and adverse effects. Large databases of summary level genetic association data are increasingly available and can be leveraged to identify and validate variants that serve as proxies for drug target perturbation. As with all empirical research, Mendelian randomization has limitations including genetic confounding, its consideration of lifelong effects, and issues related to heterogeneity across different tissues and populations. When appropriately applied, Mendelian randomization provides a useful empirical framework for using population level data to improve the success rates of the drug development pipeline.
Highlights
The majority of small molecule and biologic drugs exert their effects by perturbing protein targets[1]
For drug target Mendelian randomization (MR) genetic variants such as singlenucleotide polymorphisms (SNPs) related to the function or expression of the drug target protein can be used as instrumental variables to study the effect of perturbing that drug target[25,26]
We describe issues relating to selection of genetic variants as proxies for drug target perturbation, evaluation of the plausibility of genetic variants as proxies for drug target perturbation, generation and interpretation of MR estimates, and limitations of MR for investigating drug target perturbation
Summary
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