MultiSuSiE improves multi-ancestry fine-mapping in All of Us whole-genome sequencing data

Abstract Leveraging data from multiple ancestries can greatly improve fine-mapping power due to differences in linkage disequilibrium and allele frequencies. We propose MultiSuSiE, an extension of the sum of single effects model (SuSiE) to multiple ancestries that allows causal effect sizes to vary across ancestries based on a multivariate normal prior informed by empirical data. We evaluated MultiSuSiE via simulations and analyses of 14 quantitative traits leveraging whole-genome sequencing data in 47k African-ancestry and 94k European-ancestry individuals from All of Us. In simulations, MultiSuSiE applied to Afr47k+Eur47k was well-calibrated and attained higher power than SuSiE applied to Eur94k; interestingly, higher causal variant PIPs in Afr47k compared to Eur47k were entirely explained by differences in the extent of LD quantified by LD 4th moments. Compared to very recently proposed multi-ancestry fine-mapping methods, MultiSuSiE attained higher power and/or much lower computational costs, making the analysis of large-scale All of Us data feasible. In real trait analyses, MultiSuSiE applied to Afr47k+Eur94k identified 579 fine-mapped variants with PIP > 0.5, and MultiSuSiE applied to Afr47k+Eur47k identified 44% more fine-mapped variants with PIP > 0.5 than SuSiE applied to Eur94k. We validated MultiSuSiE results for real traits via functional enrichment of fine-mapped variants. We highlight several examples where MultiSuSiE implicates well-studied or biologically plausible fine-mapped variants that were not implicated by other methods.