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

Genome Aggregation Database Production Team, Genome Aggregation Database Consortium

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)459-464
Number of pages6
Issue number7809
StatePublished - 28 May 2020

Bibliographical note

Funding Information:
Author contributions Conceived and designed the study: E.V.M., S.L.S., D.G.M. Performed analysis: E.V.M., K.J.K., H.C.M., B.B.C., N.W., D.R. Supervised the research: J.A., R.C.T., D.A.v.H., M.J.D., S.L.S., D.G.M. Provided data: gnomAD consortium (Genome Aggregation Database Production Team and Genome Aggregation Database Consortium), H.C.M., R.C.T., D.A.v.H. Wrote the paper: E.V.M. Edited and approved the final manuscript: all authors Competing interests E.V.M. has received research support in the form of charitable contributions from Charles River Laboratories and Ionis Pharmaceuticals, and has consulted for Deerfield Management. K.J.K. is a shareholder of Personalis. H.C.M., B.B.C., M.W., D.R. and J.A. have no competing interests to declare. R.C.T. serves on the Scientific Advisory Board of Ipsen Ltd and has current funding from the Wellcome Trust and the National Institute for Health Research UK. D.A.v.H. is a shareholder of Nexpep Pty Ltd; has current or recent research funding from Wellcome Trust, Medical Research Council UK, National Institute for Health Research UK, Alnylam Pharmaceuticals; and serves on the Population & Systems Medicine Board of the Medical Research Council UK. MJD is a founder of Maze Therapeutics. S.L.S. serves on the Board of Directors of the Genomics Institute of the Novartis Research Foundation (‘GNF’); is a shareholder and serves on the Board of Directors of Jnana Therapeutics; is a shareholder of Forma Therapeutics; is a shareholder and advises Decibel Therapeutics and Eikonizo Therapeutics; serves on the Scientific Advisory Boards of Eisai Co., Ltd., Ono Pharma Foundation, Exo Therapeutics, and F-Prime Capital Partners; and is a Novartis Faculty Scholar. D.G.M. is a founder with equity in Goldfinch Bio, and has received research support from AbbVie, Astellas, Biogen, BioMarin, Eisai, Merck, Pfizer, and Sanofi-Genzyme.

Funding Information:
Acknowledgements This study was performed under ethical approval from the Partners Healthcare Institutional Research Board (2013P001339/MGH) and the Broad Institute Office of Research Subjects Protection (ORSP-3862) in compliance with all relevant ethical regulations; written informed consent was obtained from all research participants. We thank all of the research participants for contributing their data. E.V.M. acknowledges support from the National Institutes of Health (NIH) (F31 AI122592) and an anonymous organization. gnomAD data aggregation was supported primarily by the Broad Institute, gnomAD analysis was supported in part by NIDDK U54 DK105566, and development of LOFTEE by NIGMS R01 GM104371. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. E.L.G.H. is funded by the Wellcome Trust (102627, 210561), the Medical Research Council (M009017), Higher Education Funding Council for England Catalyst, Barts Charity (845/1796), Health Data Research UK (for London substantive site), and research delivery support from the NHS National Institute for Health Research Clinical Research Network (North Thames). N.W. is supported by a Rosetrees and Stoneygate Imperial College Research Fellowship. The results published here are in part based upon data: (1) generated by The Cancer Genome Atlas managed by the NCI and NHGRI (accession: phs000178.v10.p8). Information about TCGA can be found at http://cancergenome.nih.gov; (2) generated by the Genotype-Tissue Expression Project (GTEx) managed by the NIH Common Fund and NHGRI (accession: phs000424.v7.p2); (3) generated by the Exome Sequencing Project, managed by NHLBI; (4) generated by the Alzheimer’s Disease Sequencing Project (ADSP), managed by the NIA and NHGRI (accession: phs000572.v7.p4). We thank J. Kaprio and M. Kurki (Finnish Twins AD cohort) and Academy of Finland grant 312073, and Ruth McPherson (Ottawa Genomics Heart Study) for providing information on individuals with PRNP-truncating variants. We thank J. B. Carroll, K. Heilbron, J. Fah Sathirapongsasuti, and L. C. Francioli for comments and suggestions. A subset of the analyses reported here originally appeared as a blog post on CureFFI.org (http://www.cureffi.org/2018/09/12/lof-and-drug-safety/).

Publisher Copyright:
© 2020, The Author(s).

ASJC Scopus subject areas

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