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Mendelian randomization for studying the effects of perturbing drug targets [version 2; peer review: 3 approved, 1 approved with reservations]

Gill, D; Georgakis, MK; Walker, VM; Schmidt, AF; Gkatzionis, A; Freitag, DF; Finan, C; ... Davies, NM; + view all (2021) Mendelian randomization for studying the effects of perturbing drug targets [version 2; peer review: 3 approved, 1 approved with reservations]. Wellcome Open Research , 6 , Article 16. 10.12688/wellcomeopenres.16544.2. Green open access

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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.

Type: Article
Title: Mendelian randomization for studying the effects of perturbing drug targets [version 2; peer review: 3 approved, 1 approved with reservations]
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.12688/wellcomeopenres.16544.2
Publisher version: http://doi.org/10.12688/wellcomeopenres.16544.2
Language: English
Additional information: 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. http://creativecommons.org/licenses/by/4.0/
Keywords: Drugs, Genetics, Mendelian randomization
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Population Science and Experimental Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/10122440
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