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Mendelian randomization for studying the effects of perturbing drug targets.

Gill, D; Georgakis, MK; Walker, VM; Schmidt, AF; Gkatzionis, A; Freitag, DF; Finan, C; Hingorani, AD; Howson, JMM; Burgess, S; et al. 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 (2021) Mendelian randomization for studying the effects of perturbing drug targets. Wellcome Open Res, 6. p. 16. ISSN 2398-502X https://doi.org/10.12688/wellcomeopenres.16544.2
SGUL Authors: Gill, Dipender Preet Singh

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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.

Item Type: Article
Additional Information: Copyright: © 2021 Gill D et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Drugs, Genetics, Mendelian randomization
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: Wellcome Open Res
ISSN: 2398-502X
Language: eng
Dates:
DateEvent
10 February 2021Published
1 February 2021Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
203928/Z/16/ZWellcome Trusthttp://dx.doi.org/10.13039/100004440
R01 HL105756NHLBI NIH HHSUNSPECIFIED
CL-2020-16-001National Institute for Health Researchhttp://dx.doi.org/10.13039/501100000272
RG88311Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
666881Horizon 2020UNSPECIFIED
667375Horizon 2020UNSPECIFIED
204623/Z/16/ZWellcome Trusthttp://dx.doi.org/10.13039/100004440
FS/18/23/33512British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
MC_UU_12013/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
MC_UU_12013/9Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
MC_UU_00011/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
295989Norwegian Research CouncilUNSPECIFIED
RE/18/4/34215British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
PubMed ID: 33644404
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/113015
Publisher's version: https://doi.org/10.12688/wellcomeopenres.16544.2

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