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


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.

Type Journal
ISBN 1476-4687 (Electronic) 0028-0836 (Linking)
Authors Minikel, E. V.; Karczewski, K. J.; Martin, H. C.; Cummings, B. B.; Whiffin, N.; Rhodes, D.; Alfoldi, J.; Trembath, R. C.; van Heel, D. A.; Daly, M. J.; Genome Aggregation Database Production, Team; Genome Aggregation Database, Consortium; Schreiber, S. L.; MacArthur, D. G.
Responsible Garvan Author Prof Daniel MacArthur
Publisher Name NATURE
Published Date 2020-05-31
Published Volume 581
Published Issue 7809
Published Pages 459-464
Status Published in-print
DOI 10.1038/s41586-020-2267-z
URL link to publisher's version