TY - JOUR
KW - Artifacts
KW - Automation
KW - Consanguinity
KW - Exons
KW - Gain of Function Mutation
KW - Gene Frequency
KW - Gene Knockdown Techniques
KW - Genes, Essential
KW - Heterozygote
KW - Homozygote
KW - Humans
KW - Huntingtin Protein
KW - Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
KW - Loss of Function Mutation
KW - Molecular Targeted Therapy
KW - Neurodegenerative Diseases
KW - Prion Proteins
KW - Reproducibility of Results
KW - Sample Size
KW - tau Proteins
AU - Eric Vallabh Minikel
AU - Konrad J. Karczewski
AU - Hilary C. Martin
AU - Beryl B. Cummings
AU - Nicola Whiffin
AU - Daniel Rhodes
AU - Jessica Alföldi
AU - Richard C. Trembath
AU - David A. van Heel
AU - Mark J. Daly
AU - Genome Aggregation Database Production Team
AU - Genome Aggregation Database Consortium
AU - Stuart L. Schreiber
AU - Daniel G. MacArthur
AB - 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.
BT - Nature
DA - 2020-05
DO - 10.1038/s41586-020-2267-z
IS - 7809
LA - eng
N2 - 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.
PY - 2020
SP - 459
EP - 464
T2 - Nature
TI - Evaluating drug targets through human loss-of-function genetic variation
VL - 581
SN - 1476-4687
ER -