Mendelian randomization for studying the effects of perturbing drug targets.
Wellcome Open Res. 2021 Feb 10;6:16. doi: 10.12688/wellcomeopenres.16544.2. PMID: 33644404; PMCID: PMC7903200.
|Authors/Editors:||Gill D, Georgakis MK, Walker VM, Schmidt AF, Gkatzionis A, Freitag DF, Finan C, Hingorani AD, Howson JMM, Burgess S, Swerdlow DI, Davey Smith G, Holmes MV, Dichgans M. Scott RA, Zheng J, Psaty BM, Davies NM.|
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.
Keywords: Drugs, Genetics, Mendelian randomization