近日，美国麻省总医院Daniel G. MacArthur、Eric Vallabh Minikel等研究人员合作发现，人类功能丧失的遗传变异可用于评估药物靶标。这一研究成果发表在2020年5月27日出版的国际学术期刊《自然》上。
Title: Evaluating drug targets through human loss-of-function genetic variation
Author: Eric Vallabh Minikel, Konrad J. Karczewski, Hilary C. Martin, Beryl B. Cummings, Nicola Whiffin, Daniel Rhodes, Jessica Alfldi, Richard C. Trembath, David A. van Heel, Mark J. Daly, Stuart L. Schreiber, Daniel G. MacArthur
Abstract: 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.