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Evaluating drug tar...
Evaluating drug targets through human loss-of-function genetic variation
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- Vallabh Minikel, Eric (author)
- Broad Institute,Massachusetts General Hospital
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- MacArthur, Daniel G (author)
- Broad Institute,Massachusetts General Hospital
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- Groop, Leif (creator_code:cre_t)
- Lund University,Lunds universitet,Genomik, diabetes och endokrinologi,Forskargrupper vid Lunds universitet,Genomics, Diabetes and Endocrinology,Lund University Research Groups
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- Haiman, Christopher (creator_code:cre_t)
- Lund University
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- Melander, Olle (creator_code:cre_t)
- Lund University,Lunds universitet,Kardiovaskulär forskning - hypertoni,Forskargrupper vid Lunds universitet,Cardiovascular Research - Hypertension,Lund University Research Groups,Skåne University Hospital
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- Nilsson, Peter M (creator_code:cre_t)
- Lund University,Lunds universitet,Internmedicin - epidemiologi,Forskargrupper vid Lunds universitet,Internal Medicine - Epidemiology,Lund University Research Groups,Skåne University Hospital
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(creator_code:org_t)
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- 2020-05-27
- 2020
- English 6 s.
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 581, s. 459-464
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Abstract
Subject headings
Close
- 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.
Subject headings
- NATURVETENSKAP -- Biologi -- Genetik (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Genetics (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
Keyword
- automation
- cell
- drug
- genetic variation
- genotype
Publication and Content Type
- art (subject category)
- ref (subject category)
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