Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

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

View ORCID ProfileEric Vallabh Minikel, View ORCID ProfileKonrad J Karczewski, View ORCID ProfileHilary C Martin, View ORCID ProfileBeryl B Cummings, View ORCID ProfileNicola Whiffin, Daniel Rhodes, View ORCID ProfileJessica Alföldi, View ORCID ProfileRichard C Trembath, View ORCID ProfileDavid A van Heel, Mark J Daly, Genome Aggregation Database Production Team, Genome Aggregation Database Consortium, View ORCID ProfileStuart L Schreiber, Daniel G MacArthur
doi: https://doi.org/10.1101/530881
Eric Vallabh Minikel
1Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
2Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, 02114, USA
3Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, 02115, USA
4Prion Alliance, Cambridge, MA, 02139, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Eric Vallabh Minikel
  • For correspondence: eminikel@broadinstitute.org danmac@broadinstitute.org
Konrad J Karczewski
1Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
2Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, 02114, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Konrad J Karczewski
Hilary C Martin
5Wellcome Sanger Institute, Hinxton, Cambridgeshire, CB10 1SA, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Hilary C Martin
Beryl B Cummings
1Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
2Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, 02114, USA
3Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, 02115, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Beryl B Cummings
Nicola Whiffin
1Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
6National Heart and Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, London, SW7 2AZ, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Nicola Whiffin
Daniel Rhodes
7Centre for Translational Bioinformatics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London and Barts Health NHS Trust, London, EC1M 6BQ, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jessica Alföldi
1Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
2Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, 02114, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Jessica Alföldi
Richard C Trembath
8Faculty of Life Sciences and Medicine, King’s College London, London, WC2R 2LS, UK
9Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, E1 2AT, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Richard C Trembath
David A van Heel
9Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, E1 2AT, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for David A van Heel
Mark J Daly
1Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
2Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, 02114, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Stuart L Schreiber
1Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
10Department of Chemistry & Chemical Biology, Harvard University, Cambridge, MA, 02138, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Stuart L Schreiber
Daniel G MacArthur
1Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
2Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, 02114, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: eminikel@broadinstitute.org danmac@broadinstitute.org
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Data/Code
  • Preview PDF
Loading

SUMMARY

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.

Footnotes

  • Extensively revised in response to peer reviewer comments.

  • https://github.com/ericminikel/drug_target_lof

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
Back to top
PreviousNext
Posted July 30, 2019.
Download PDF
Data/Code
Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Evaluating potential drug targets through human loss-of-function genetic variation
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Evaluating potential drug targets through human loss-of-function genetic variation
Eric Vallabh Minikel, Konrad J Karczewski, Hilary C Martin, Beryl B Cummings, Nicola Whiffin, Daniel Rhodes, Jessica Alföldi, Richard C Trembath, David A van Heel, Mark J Daly, Genome Aggregation Database Production Team, Genome Aggregation Database Consortium, Stuart L Schreiber, Daniel G MacArthur
bioRxiv 530881; doi: https://doi.org/10.1101/530881
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
Evaluating potential drug targets through human loss-of-function genetic variation
Eric Vallabh Minikel, Konrad J Karczewski, Hilary C Martin, Beryl B Cummings, Nicola Whiffin, Daniel Rhodes, Jessica Alföldi, Richard C Trembath, David A van Heel, Mark J Daly, Genome Aggregation Database Production Team, Genome Aggregation Database Consortium, Stuart L Schreiber, Daniel G MacArthur
bioRxiv 530881; doi: https://doi.org/10.1101/530881

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Genomics
Subject Areas
All Articles
  • Animal Behavior and Cognition (4119)
  • Biochemistry (8828)
  • Bioengineering (6532)
  • Bioinformatics (23486)
  • Biophysics (11806)
  • Cancer Biology (9223)
  • Cell Biology (13336)
  • Clinical Trials (138)
  • Developmental Biology (7444)
  • Ecology (11425)
  • Epidemiology (2066)
  • Evolutionary Biology (15174)
  • Genetics (10453)
  • Genomics (14056)
  • Immunology (9188)
  • Microbiology (22200)
  • Molecular Biology (8823)
  • Neuroscience (47627)
  • Paleontology (351)
  • Pathology (1431)
  • Pharmacology and Toxicology (2493)
  • Physiology (3736)
  • Plant Biology (8090)
  • Scientific Communication and Education (1438)
  • Synthetic Biology (2225)
  • Systems Biology (6042)
  • Zoology (1254)