Back to Search Start Over

Author Correction: Evaluating drug targets through human loss-of-function genetic variation

Authors :
Beryl B. Cummings
Richard C. Trembath
Jessica Alföldi
David A. van Heel
Genome Aggregation Database Production Team
Hilary C. Martin
Nicola Whiffin
Daniel G. MacArthur
Stuart L. Schreiber
Eric Vallabh Minikel
Konrad J. Karczewski
Mark J. Daly
Daniel R. Rhodes
Source :
Nature
Publication Year :
2021
Publisher :
Nature Publishing Group UK, 2021.

Abstract

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.

Details

Language :
English
ISSN :
14764687 and 00280836
Volume :
590
Issue :
7846
Database :
OpenAIRE
Journal :
Nature
Accession number :
edsair.doi.dedup.....bdb7b91308d3a6ab36e0018ddbe2158a