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Evaluating drug targets through human loss-of-function genetic variation

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journal contribution
posted on 05.07.2021, 22:27 by EV Minikel, KJ Karczewski, HC Martin, BB Cummings, N Whiffin, D Rhodes, J Alföldi, RC Trembath, DA van Heel, MJ Daly, Genome Aggregation Database Production Team, Genome Aggregation Database Consortium, SL Schreiber, DG MacArthur
Naturally occurring human genetic variants that are predicted to inactivate protein-coding genes provide an in vivo model of human gene inactivation that complements knockout studies in cells and model organisms. Here we report three key findings regarding the assessment of candidate drug targets using human loss-of-function variants. First, even essential genes, in which loss-of-function variants are not tolerated, can be highly successful as targets of inhibitory drugs. Second, in most genes, loss-of-function variants are sufficiently rare that genotype-based ascertainment of homozygous or compound heterozygous ‘knockout’ humans will await sample sizes that are approximately 1,000 times those presently available, unless recruitment focuses on consanguineous individuals. Third, automated variant annotation and filtering are powerful, but manual curation remains crucial for removing artefacts, and is a prerequisite for recall-by-genotype efforts. Our results provide a roadmap for human knockout studies and should guide the interpretation of loss-of-function variants in drug development.

History

Citation

Nature volume 581, pages 459–464 (2020)

Author affiliation

Department of Cardiovascular Sciences and NIHR Leicester Biomedical Research Centre

Version

VoR (Version of Record)

Published in

Nature

Volume

581

Issue

7809

Pagination

459 - 464

Publisher

Nature Research

issn

0028-0836

eissn

1476-4687

Acceptance date

10/02/2020

Copyright date

2020

Available date

05/07/2021

Spatial coverage

England

Language

English