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, View ORCID ProfileJessica Alföldi, View ORCID ProfileRichard C Trembath, View ORCID ProfileDavid A van Heel, Mark J Daly, Genome Aggregation Database Production Team, 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
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
7Faculty of Life Sciences and Medicine, King’s College London, London, WC2R 2LS, UK
8Blizard 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
8Blizard 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
9Department 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
  • Preview PDF
Loading

Abstract

Human genetics has informed the clinical development of new drugs, and is beginning to influence the selection of new drug targets. Large-scale DNA sequencing studies have created a catalogue of naturally occurring genetic variants predicted to cause loss of function in human genes, which in principle should provide powerful in vivo models of human genetic “knockouts” to complement model organism knockout studies and inform drug development. Here, we consider the use of predicted loss-of-function (pLoF) variation catalogued in the Genome Aggregation Database (gnomAD) for the evaluation of genes as potential drug targets. Many drug targets, including the targets of highly successful inhibitors such as aspirin and statins, are under natural selection at least as extreme as known haploinsufficient genes, with pLoF variants almost completely depleted from the population. Thus, metrics of gene essentiality should not be used to eliminate genes from consideration as potential targets. The identification of individual humans harboring “knockouts” (biallelic gene inactivation), followed by individual recall and deep phenotyping, is highly valuable to study gene function. In most genes, pLoF alleles are sufficiently rare that ascertainment will be largely limited to heterozygous individuals in outbred populations. Sampling of diverse bottlenecked populations and consanguineous individuals will aid in identification of total “knockouts”. Careful filtering and curation of pLoF variants in a gene of interest is necessary in order to identify true LoF individuals for follow-up, and the positional distribution or frequency of true LoF variants may reveal important disease biology. Our analysis suggests that the value of pLoF variant data for drug discovery lies in deep curation informed by the nature of the drug and its indication, as well as the biology of the gene, followed by recall-by-genotype studies in targeted populations.

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 January 29, 2019.
Download PDF
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, Jessica Alföldi, Richard C Trembath, David A van Heel, Mark J Daly, Genome Aggregation Database Production Team, Stuart L Schreiber, Daniel G MacArthur
bioRxiv 530881; doi: https://doi.org/10.1101/530881
Reddit logo Twitter logo Facebook 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, Jessica Alföldi, Richard C Trembath, David A van Heel, Mark J Daly, Genome Aggregation Database Production Team, 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 (4395)
  • Biochemistry (9619)
  • Bioengineering (7111)
  • Bioinformatics (24915)
  • Biophysics (12642)
  • Cancer Biology (9980)
  • Cell Biology (14388)
  • Clinical Trials (138)
  • Developmental Biology (7977)
  • Ecology (12135)
  • Epidemiology (2067)
  • Evolutionary Biology (16010)
  • Genetics (10938)
  • Genomics (14764)
  • Immunology (9889)
  • Microbiology (23719)
  • Molecular Biology (9493)
  • Neuroscience (50969)
  • Paleontology (370)
  • Pathology (1544)
  • Pharmacology and Toxicology (2688)
  • Physiology (4031)
  • Plant Biology (8685)
  • Scientific Communication and Education (1512)
  • Synthetic Biology (2403)
  • Systems Biology (6446)
  • Zoology (1346)