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

By Eric Vallabh Minikel, Konrad Karczewski, Hilary C Martin, Beryl B. Cummings, Nicola Whiffin, Daniel Rhodes, Jessica Alföldi, Richard C. Trembath, David A. van Heel, M. Daly, Genome Aggregation Database Production Team, Genome Aggregation Database Consortium, Stuart L Schreiber, Daniel G MacArthur

Posted 28 Jan 2019
bioRxiv DOI: 10.1101/530881 (published DOI: 10.1038/s41586-020-2267-z)

Naturally occurring human genetic variants predicted to cause loss of function of protein-coding genes provide an in vivo model of human gene inactivation that complements cell and model organism knockout studies. Here we investigate the application of human loss-of-function variants to assess genes as candidate drug targets, with three key findings. First, even essential genes, where 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 ~1,000 times those available at present. Third, automated variant annotation and filtering are powerful, but manual curation remains critical for removing artifacts and making biological inferences, and is a prerequisite for recall-by-genotype efforts. Our results provide a roadmap for human “knockout” studies and should guide interpretation of loss-of-function variants in drug development.

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