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

Area of Science:

• Genomics
• Pharmacogenomics
• Population Genetics

Background:

• Historical genetic studies are limited by ancestral bias, leaving functional variations understudied.
• Integrating diverse human genetics 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 potential therapeutic targets by leveraging the NIH All of Us Research Program data.

Main Methods:

• Genome-wide association studies (GWAS) for common variants and rare-variant burden testing were performed across 624 quantitative traits.
• Fine-mapping and computational variant-effect prediction were used to prioritize causal rare variants.
• Joint modeling of common and rare variation, incorporating protein-class annotations, was employed.

Main Results:

• Identified 6,181 genome-wide significant locus-trait associations (526 novel) and 416 gene-trait associations (105 novel).
• Prioritized rare, likely causal variants driving association signals.
• Demonstrated improved identification of drug targets by jointly modeling common and rare variation compared to common-variant analysis alone.

Conclusions:

• Characterizing both rare and common genetic variation in diverse populations enhances causal gene discovery.
• Identified novel, actionable therapeutic targets, such as NRG4 for kidney function preservation.
• This approach accelerates drug development by addressing ancestral biases in genetic data.