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

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From: Nature(Vol. 581, Issue 7809)
Publisher: Nature Publishing Group
Document Type: Clinical report
Length: 9,224 words
Lexile Measure: 1630L

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Author(s): Eric Vallabh Minikel 1 2 3 4 5 6 7 8 , Konrad J. Karczewski 1 4 , Hilary C. Martin 9 , Beryl B. Cummings 1 4 5 , Nicola Whiffin 1 10 , Daniel Rhodes 11 , Jessica Alföldi 1 4 , Richard C. Trembath 12 , David A. van Heel 13 , Mark J. Daly 1 4 , Jessica Alföldi 1 4 , Irina M. Armean 1 4 15 , Eric Banks 16 , Louis Bergelson 16 , Kristian Cibulskis 16 , Ryan L. Collins 1 17 18 , Kristen M. Connolly 19 , Miguel Covarrubias 16 , Beryl B. Cummings 1 4 5 , Mark J. Daly 1 4 , Stacey Donnelly 1 , Yossi Farjoun 16 , Steven Ferriera 20 , Laurent Francioli 1 4 , Stacey Gabriel 20 , Laura D. Gauthier 16 , Jeff Gentry 16 , Namrata Gupta 1 20 , Thibault Jeandet 16 , Diane Kaplan 16 , Konrad J. Karczewski 1 4 , Kristen M. Laricchia 1 4 , Christopher Llanwarne 16 , Eric V. Minikel 1 2 4 , Ruchi Munshi 16 , Benjamin M. Neale 1 4 , Sam Novod 16 , Anne H. O'Donnell-Luria 1 21 22 , Nikelle Petrillo 16 , Timothy Poterba 1 2 4 , David Roazen 16 , Valentin Ruano-Rubio 16 , Andrea Saltzman 1 , Kaitlin E. Samocha 9 , Molly Schleicher 1 , Cotton Seed 2 4 , Matthew Solomonson 1 4 , Jose Soto 16 , Grace Tiao 1 4 , Kathleen Tibbetts 16 , Charlotte Tolonen 16 , Christopher Vittal 2 4 , Gordon Wade 16 , Arcturus Wang 1 2 4 , Qingbo Wang 1 4 18 , James S. Ware 1 23 24 , Nicholas A. Watts 1 4 , Ben Weisburd 16 , Nicola Whiffin 1 23 24

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Human genetics is an increasingly crucial source of evidence guiding the selection of new targets for drug discovery1 . Most new clinical drug candidates eventually fail for lack of efficacy2 , and although in vitro, cell culture and animal model systems can provide preclinical evidence that the compound engages its target, too often the target itself is not causally related to human disease1 . Candidates targeting genes with human genetic evidence for disease causality are more likely to reach approval3,4 , and identification of humans with loss-of-function (LoF) variants, particularly two-hit (homozygous or compound heterozygous) genotypes, has, for several genes, correctly predicted the safety and phenotypic effect of pharmacological inhibition5 . Although these examples demonstrate the value of human genetics in drug development, important questions remain regarding strategies for identifying individuals with LoF variants in a gene of interest, interpretation of the frequency--or lack--of such individuals, and whether it is wise to pharmacologically target a gene in which LoF variants are associated with a deleterious phenotype.

Public databases of human genetic variation have catalogued predicted loss-of-function (pLoF) variants--nonsense, essential splice site, and frameshift variants expected to result in a non-functional allele. This presents an opportunity to study the effects of pLoF variation in genes of interest and to identify individuals with pLoF genotypes to understand gene function or disease biology, or to assess potential for therapeutic targeting. Although many variants initially annotated as pLoF do not, in fact, abolish gene function6 , rigorous automated filtering can remove common error modes7 . True LoF variants are generally rare, and show important differences between outbred, bottlenecked8 and consanguineous9 populations6,10 . Counting...

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Gale Document Number: GALE|A625089923