ArticleNature2020
Evaluating drug targets through human loss-of-function genetic variation.
Article in Nature, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 108 papers, 3 of them syntheses that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
108 citing papers in PubMed, 3 syntheses or guidelines pooled it.
- Meta-analysis across six global biobanks identifies recessive coding associations with complex traits and diseases.American journal of human genetics · 2026Pooled it
- The genomic architecture of circulating cytokine levels points to drug targets for immune-related diseases.Communications biology · 2025Pooled it
- Association of germline TYK2 variation with lung cancer and non-Hodgkin lymphoma risk.International journal of cancer · 2022Pooled it
- Genome-scale perturbation signatures from primary human CD4bioRxiv : the preprint server for biology · 2026Article
- Reduced dosage of Kmt2d modifies Tbx1 haploinsufficiency toward phenotypes of 22q11.2DS.JCI insight · 2026Article
- Article
- Machine Learning Reveals the Contribution of Rare Genetic Variants and Enhances Risk Prediction for Coronary Artery Disease in the Japanese Population.Circulation. Genomic and precision medicine · 2026Article
- A blended genome and exome sequencing method captures genetic variation in an unbiased and cost-effective manner.Nature genetics · 2026Article
- AllTheBacteria: a community resource empowers biology and discovers novel peptide antibiotics.bioRxiv : the preprint server for biology · 2026Article
- Drug targets for lipid modification and risk of type 2 diabetes: a cis-Mendelian randomization study.Cardiovascular diabetology · 2026Article
- Divalent siRNA for prion disease.Nucleic acids research · 2026Article
- Functional insights into dispensable genes using genome-wide loss-of-function burden tests in Arabidopsis.The Plant cell · 2026Article
- Exome sequencing and analysis of 44,028 British South Asians enriched for high autozygosity.Nature genetics · 2026Article
- Whole-genome sequencing of 3135 individuals representing the genetic diversity of the Japanese population.Journal of human genetics · 2026Article
- Genetic Variation in the Chemokine Network and Atherosclerosis Risk.Current atherosclerosis reports · 2026Review
- The features and prognostic value of ARID1A mutation and protein expression in endometrial cancer of no specific molecular profile (NSMP) subtype: a retrospective study in a large Chinese cohort.Journal of cancer research and clinical oncology · 2026Article
- Divalent siRNA for prion disease.bioRxiv : the preprint server for biology · 2026Article
- Article
- Inherited resilience to clonal hematopoiesis by modifying stem cell RNA regulation.Science (New York, N.Y.) · 2026Article
- Characterizing common loss-of-function genes and their potential utility in assessing population variability and chemical susceptibility.bioRxiv : the preprint server for biology · 2025Article
48 more citing papers are in PubMed but not listed here.
Corrections and comments
- Commented on by
- Commented on by
- Erratum issued
Authors and funding
14 authors.
Funding
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.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.