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

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Vallabh Minikel, Eric (author): Broad Institute,Massachusetts General Hospital

MacArthur, Daniel G (author): Broad Institute,Massachusetts General Hospital

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

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

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

(creator_code:org_t)

2020-05-27
2020
English 6 s.
In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 581, s. 459-464

Related links:: http://dx.doi.org/10... (free); show more...; https://www.nature.c...; https://lup.lub.lu.s...; https://doi.org/10.1...; show less...

Abstract Subject headings

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.

By the author/editor: Vallabh Minikel, ...; MacArthur, Danie ...; Groop, Leif; Haiman, Christop ...; Melander, Olle; Nilsson, Peter M

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Medical Genetics

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