Using Human Genetics to Drive Drug Discovery: A Perspective.

The probability of success of developing medicines to treat human disease can be improved by leveraging human genetics. Different types of genetic data and techniques, including genome-wide association, whole-exome sequencing, and whole-genome sequencing, can be used to gain insight into human disease. Layering different types of genetic evidence from Mendelian disease, coding variants, and common variation can bolster support for a genetic target. Human knockouts offer the potential to perform reverse genetic screens in humans to identify physiologically relevant targets. Other components of a good genetic target include protective loss-of-function mutations, some degree of known biology, tractability, and a clean on-target safety profile. In addition to using human genetics to inspire new drug programs, phenome-wide association studies can be used to identify alternative indications or repurposing opportunities. This information can be combined into a 5-step approach for selecting a genetic target for validation, which is presented in detail in this review. Finally, current challenges in leveraging human genetics are highlighted, including the difficulties translating certain types of genetic data, relatively small number of bona fide disease-associated coding rare variants, and current sample sizes of large well-curated biobanks linked to comprehensive genetic information.