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Mendelian randomization for studying the effects of perturbing drug targets. 2021
Dipender Gill, and
Marios K Georgakis, and
Venexia M Walker, and
A Floriaan Schmidt, and
Apostolos Gkatzionis, and
Daniel F Freitag, and
Chris Finan, and
Aroon D Hingorani, and
Joanna M M Howson, and
Stephen Burgess, and
Daniel I Swerdlow, and
George Davey Smith, and
Michael V Holmes, and
Martin Dichgans, and
Robert A Scott, and
Jie Zheng, and
Bruce M Psaty, and
Neil M Davies
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
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.
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