Integrating multi-ancestry common and rare variant mapping accelerates therapeutic target discovery

Area of Science:

• Genomics
• Pharmacogenomics
• Population Genetics

Background:

• Historical genetic studies often lack ancestral diversity, limiting the discovery of functional variations.
• Understanding genetic contributions to traits is crucial for advancing therapeutic discovery and drug development.

Purpose of the Study:

• To conduct comprehensive association analyses of common and rare genetic variants across diverse populations.
• To identify novel gene-trait associations and prioritize causal variants for therapeutic targeting.

Main Methods:

• Leveraged the NIH All of Us Research Program data from 369,655 diverse individuals.
• Performed genome-wide association studies (GWAS) for common variants and rare-variant burden testing for 624 quantitative traits.
• Integrated fine-mapping and computational variant-effect prediction for causal variant prioritization.

Main Results:

• Identified 6,181 genome-wide significant locus-trait associations (526 novel) and 416 gene-trait associations (105 novel).
• Demonstrated that joint modeling of common and rare variation improved the identification of known drug targets.
• Highlighted NRG4 as a high-confidence candidate therapeutic target for kidney function preservation.

Conclusions:

• Characterizing both rare and common genetic variation in diverse populations enhances causal gene discovery.
• This approach identifies novel and actionable therapeutic targets, advancing precision medicine.
• The findings underscore the importance of diversity in genetic research for equitable drug development.