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

Author

Listed:
  • Eric Vallabh Minikel

    (Broad Institute of MIT and Harvard
    Broad Institute of MIT and Harvard
    Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Konrad J. Karczewski

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Hilary C. Martin

    (Wellcome Sanger Institute)

  • Beryl B. Cummings

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Harvard Medical School)

  • Nicola Whiffin

    (Broad Institute of MIT and Harvard
    Imperial College London)

  • Daniel Rhodes

    (Queen Mary University of London and Barts Health NHS Trust)

  • Jessica Alföldi

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Richard C. Trembath

    (King’s College London)

  • David A. Heel

    (Queen Mary University of London)

  • Mark J. Daly

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Stuart L. Schreiber

    (Broad Institute of MIT and Harvard
    Harvard University)

  • Daniel G. MacArthur

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Garvan Institute of Medical Research and UNSW Sydney
    Murdoch Children’s Research Institute)

Abstract

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.

Suggested Citation

  • Eric Vallabh Minikel & Konrad J. Karczewski & Hilary C. Martin & Beryl B. Cummings & Nicola Whiffin & Daniel Rhodes & Jessica Alföldi & Richard C. Trembath & David A. Heel & Mark J. Daly & Stuart L. S, 2020. "Evaluating drug targets through human loss-of-function genetic variation," Nature, Nature, vol. 581(7809), pages 459-464, May.
  • Handle: RePEc:nat:nature:v:581:y:2020:i:7809:d:10.1038_s41586-020-2267-z
    DOI: 10.1038/s41586-020-2267-z
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    Cited by:

    1. Chang Lu & Jan Zaucha & Rihab Gam & Hai Fang & Smithers & Matt E. Oates & Miguel Bernabe-Rubio & James Williams & Natalie Zelenka & Arun Prasad Pandurangan & Himani Tandon & Hashem Shihab & Raju Kalai, 2023. "Hypothesis-free phenotype prediction within a genetics-first framework," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Elena Arciero & Sufyan A. Dogra & Daniel S. Malawsky & Massimo Mezzavilla & Theofanis Tsismentzoglou & Qin Qin Huang & Karen A. Hunt & Dan Mason & Saghira Malik Sharif & David A. Heel & Eamonn Sherida, 2021. "Fine-scale population structure and demographic history of British Pakistanis," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    3. Keith Woodley & Laura S. Dillingh & George Giotopoulos & Pedro Madrigal & Kevin M. Rattigan & Céline Philippe & Vilma Dembitz & Aoife M. S. Magee & Ryan Asby & Louie N. van de Lagemaat & Christopher M, 2023. "Mannose metabolism inhibition sensitizes acute myeloid leukaemia cells to therapy by driving ferroptotic cell death," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    4. Allan Gurtan & John Dominy & Shareef Khalid & Linh Vong & Shari Caplan & Treeve Currie & Sean Richards & Lindsey Lamarche & Daniel Denning & Diana Shpektor & Anastasia Gurinovich & Asif Rasheed & Shah, 2022. "Analyzing human knockouts to validate GPR151 as a therapeutic target for reduction of body mass index," PLOS Genetics, Public Library of Science, vol. 18(4), pages 1-13, April.

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