TY - JOUR
T1 - Evaluating drug targets through human loss-of-function genetic variation
AU - Minikel, Eric Vallabh
AU - Karczewski, Konrad J.
AU - Martin, Hilary C.
AU - Cummings, Beryl B.
AU - Whiffin, Nicola
AU - Rhodes, Daniel
AU - Alföldi, Jessica
AU - Trembath, Richard C.
AU - van Heel, David A.
AU - Daly, Mark J.
AU - Alföldi, Jessica
AU - Armean, Irina M.
AU - Banks, Eric
AU - Bergelson, Louis
AU - Cibulskis, Kristian
AU - Collins, Ryan L.
AU - Connolly, Kristen M.
AU - Covarrubias, Miguel
AU - Cummings, Beryl B.
AU - Donnelly, Stacey
AU - Farjoun, Yossi
AU - Ferriera, Steven
AU - Francioli, Laurent
AU - Gabriel, Stacey
AU - Gauthier, Laura D.
AU - Gentry, Jeff
AU - Gupta, Namrata
AU - Jeandet, Thibault
AU - Kaplan, Diane
AU - Karczewski, Konrad J.
AU - Laricchia, Kristen M.
AU - Llanwarne, Christopher
AU - Minikel, Eric V.
AU - Munshi, Ruchi
AU - Neale, Benjamin M.
AU - Novod, Sam
AU - O’Donnell-Luria, Anne H.
AU - Petrillo, Nikelle
AU - Poterba, Timothy
AU - Roazen, David
AU - Ruano-Rubio, Valentin
AU - Saltzman, Andrea
AU - Samocha, Kaitlin E.
AU - Schleicher, Molly
AU - Seed, Cotton
AU - Solomonson, Matthew
AU - Soto, Jose
AU - Tiao, Grace
AU - Tibbetts, Kathleen
AU - Atzmon, Gil
N1 - Publisher Copyright: © 2020, The Author(s).
PY - 2020/5/28
Y1 - 2020/5/28
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.
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.
UR - http://www.scopus.com/inward/record.url?scp=85085564434&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41586-020-2267-z
DO - https://doi.org/10.1038/s41586-020-2267-z
M3 - Article
C2 - 32461653
SN - 0028-0836
VL - 581
SP - 459
EP - 464
JO - Nature
JF - Nature
IS - 7809
ER -