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Olle Melander

Principal investigator

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

Author

  • Eric Vallabh Minikel
  • Daniel G MacArthur

Other contributions

  • Leif Groop
  • Christopher Haiman
  • Olle Melander
  • Peter M Nilsson

Summary, in English

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.

Department/s

  • Genomics, Diabetes and Endocrinology
  • EXODIAB: Excellence in Diabetes Research in Sweden
  • EpiHealth: Epidemiology for Health
  • Cardiovascular Research - Hypertension
  • Internal Medicine - Epidemiology

Publishing year

2020-05-27

Language

English

Pages

459-464

Publication/Series

Nature

Volume

581

Document type

Journal article

Publisher

Nature Publishing Group

Topic

  • Genetics
  • Medical Genetics

Keywords

  • automation
  • cell
  • drug
  • genetic variation
  • genotype

Status

Published

Research group

  • Genomics, Diabetes and Endocrinology
  • Cardiovascular Research - Hypertension
  • Internal Medicine - Epidemiology

ISBN/ISSN/Other

  • ISSN: 0028-0836