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

Area of Science:

• Genetics
• Pharmacology
• Human Biology

Background:

• Naturally occurring human genetic variants serve as in vivo models for gene inactivation.
• These variants complement traditional knockout studies in cellular and model organism systems.
• Assessing candidate drug targets can be informed by human loss-of-function variants.

Purpose of the Study:

• To evaluate the utility of human loss-of-function variants in identifying and validating drug targets.
• To explore the potential of essential genes, even those intolerant to loss-of-function, as drug targets.
• To assess the feasibility of genotype-based identification of human gene knockouts.

Main Methods:

• Analysis of naturally occurring human genetic variants predicted to inactivate protein-coding genes.
• Evaluation of essential genes for their viability as targets for inhibitory drugs.
• Assessment of variant rarity for genotype-based ascertainment of homozygous or compound heterozygous individuals.
• Utilizing automated variant annotation and filtering, supplemented by manual curation.

Main Results:

• Essential genes, despite intolerance to loss-of-function, can be effective drug targets.
• Identifying homozygous or compound heterozygous 'knockout' humans requires significantly larger sample sizes ( 1,000x current) unless focusing on consanguineous populations.
• Automated variant annotation is powerful but manual curation is essential for accuracy and recall-by-genotype studies.

Conclusions:

• Human loss-of-function variants are valuable for drug target assessment.
• A roadmap for human knockout studies is provided, guiding drug development interpretations.
• The study highlights strategies for leveraging genetic variation in pharmaceutical research.