Mendelian randomization for studying the effects of perturbing drug targets [version 1; peer review: awaiting peer review]
Gill, Dipender; Georgakis, Marios K.; Walker, Venexia M.; Schmidt, A. Floriaan; Gkatzionis, Apostolos; Freitag, Daniel F.; Finan, Chris; Hingorani, Aroon D.; Howson, Joanna M.M.; Burgess, Stephen; Swerdlow, Daniel I.; Smith, George Davey; Holmes, Michael V.; Dichgans, Martin; Zheng, Jie; Psaty, Bruce M.; Davies, Neil M.
(2021) Wellcome Open Research, volume 6, pp. 1 - 11
(Article)
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
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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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Keywords: Drugs, Genetics, Mendelian randomization, Medicine (miscellaneous), General Biochemistry,Genetics and Molecular Biology
ISSN: 2398-502X
Publisher: F1000 Research Ltd.
Note: Funding Information: Research Excellence (RE/18/4/34215) at Imperial College London, and by a National Institute for Health Research Clinical Lectureship at St. George's, University of London (CL-2020-16-001). MKG has received funding by the Onassis Foundation and the German Academic Exchange Service (DAAD). AG is funded by a Medical Research Council Methodology Research Panel Grant (RG88311). This project has received funding from the European Union’s Horizon 2020 research and innovation programme (No 666881, to MD,), SVDs@target (to MD) and No 667375, CoSTREAM (to MD); the DFG as part of the Munich Cluster for Systems Neurology (EXC 1010 SyNergy, to MD) and the CRC 1123 (B3, to MD); the Corona Foundation (to MD); the Fondation Leducq (Transatlantic Network of Excellence on the Pathogenesis of Small Vessel Disease of the Brain) (to MD). CF and ADH are supported by the UCL NIHR Biomedical Research Centre and UCL BHF Research Accelerator. ADH is an NIHR Senior Investigator. SB is supported by Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (204623/Z/16/Z). MVH works in a unit that receives funding from the UK Medical Research Council and is supported by a British Heart Foundation Intermediate Clinical Research Fellowship (FS/18/23/33512) and the National Institute for Health Research Oxford Biomedical Research Centre. JZ is funded by a Vice-Chancellor Fellowship from the University of Bristol. The Medical Research Council (MRC) and the University of Bristol support the MRC Integrative Epidemiology Unit (MC_UU_12013/1, MC_UU_12013/9, MC_UU_00011/1). The Norwegian Research Council support NMD grant number 295989. This work was supported by the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) National Heart, Lung, and Blood Institute (NHLBI) grant R01HL105756-09. Funding Information: Novo Nordisk. DIS is an employee of Silence Therapeutics plc. MVH has collaborated with Boehringer Ingelheim in research, and in accordance with the policy of the Clinical Trial Service Unit and Epidemiological Studies Unit (University of Oxford), did not accept any personal payment. BMP serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. NMD reports funding from the Global Research Awards into Nicotine Dependence (GRAND) which is an independent grant awarding body funded by Pfizer. All other authors declare no conflicts of interest. Funding Information: Grant information: DG is supported by the Wellcome Trust 4i Programme (203928/Z/16/Z) and British Heart Foundation Centre of Funding Information: DG is supported by the Wellcome Trust 4i Programme (203928/Z/16/Z) and British Heart Foundation Centre of Research Excellence (RE/18/4/34215) at Imperial College London, and by a National Institute for Health Research Clinical Lectureship at St. George's, University of London (CL-2020-16-001). MKG has received funding by the Onassis Foundation and the German Academic Exchange Service (DAAD). AG is funded by a Medical Research Council Methodology Research Panel Grant (RG88311). This project has received funding from the European Union?s Horizon 2020 research and innovation programme (No 666881, to MD,), SVDs@target (to MD) and No 667375, CoSTREAM (to MD); the DFG as part of the Munich Cluster for Systems Neurology (EXC 1010 SyNergy, to MD) and the CRC 1123 (B3, to MD); the Corona Foundation (to MD); the Fondation Leducq (Transatlantic Network of Excellence on the Pathogenesis of Small Vessel Disease of the Brain) (to MD). CF and ADH are supported by the UCL NIHR Biomedical Research Centre and UCL BHF Research Accelerator. ADH is an NIHR Senior Investigator. SB is supported by Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (204623/Z/16/Z). MVH works in a unit that receives funding from the UK Medical Research Council and is supported by a British Heart Foundation Intermediate Clinical Research Fellowship (FS/18/23/33512) and the National Institute for Health Research Oxford Biomedical Research Centre. JZ is funded by a Vice-Chancellor Fellowship from the University of Bristol. The Medical Research Council (MRC) and the University of Bristol support the MRC Integrative Epidemiology Unit (MC_UU_12013/1, MC_UU_12013/9, MC_UU_00011/1). The Norwegian Research Council support NMD grant number 295989. This work was supported by the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) National Heart, Lung, and Blood Institute (NHLBI) grant R01HL105756-09. Publisher Copyright: © 2021. Gill D et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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