Evaluating multi-ancestry genome-wide association methods: Statistical power, population structure, and practical implications.

The increasing availability of diverse biobanks has enabled multi-ancestry genome-wide association studies (GWASs) to enhance the discovery of genetic variants across traits and diseases. However, the choice of an optimal method remains debated, due to challenges in statistical power differences across ancestral groups and approaches to account for population structure. Two primary strategies exist: (1) pooled analysis, which combines individuals from all genetic backgrounds into a single dataset while adjusting for population stratification using principal components, increasing the sample size and statistical power but requiring careful control of population stratification; and (2) meta-analysis, which performs ancestry-group-specific GWASs and subsequently combines summary statistics, potentially capturing fine-scale population structure but facing limitations in handling admixed individuals. Using large-scale simulations with varying sample sizes and ancestry compositions, we compare these methods alongside real data analyses of eight continuous and five binary traits from the UK Biobank (N ≈ 324,000) and the All of Us Research Program (N ≈ 207,000). Our results demonstrate that pooled analysis generally exhibits better statistical power while effectively adjusting for population stratification. We further present a theoretical framework linking power differences to allele-frequency variations across populations. These findings, validated across both biobanks, highlight pooled analysis as a powerful and scalable strategy for multi-ancestry GWASs, improving genetic discovery while maintaining rigorous population structure control.