TY - JOUR
T1 - Mendelian randomization for studying the effects of perturbing drug targets [version 1; peer review
T2 - awaiting peer review]
AU - Gill, Dipender
AU - Georgakis, Marios K.
AU - Walker, Venexia M.
AU - Schmidt, A. Floriaan
AU - Gkatzionis, Apostolos
AU - Freitag, Daniel F.
AU - Finan, Chris
AU - Hingorani, Aroon D.
AU - Howson, Joanna M. M.
AU - Burgess, Stephen
AU - Swerdlow, Daniel I.
AU - Smith, George Davey
AU - Holmes, Michael V.
AU - Dichgans, Martin
AU - Zheng, Jie
AU - Psaty, Bruce M.
AU - Davies, Neil M.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85117914557&origin=inward
U2 - https://doi.org/10.12688/WELLCOMEOPENRES.16544.1
DO - https://doi.org/10.12688/WELLCOMEOPENRES.16544.1
M3 - Article
SN - 2398-502X
VL - 6
SP - 1
EP - 11
JO - Wellcome open research
JF - Wellcome open research
ER -