Redefining replication in multi-ancestry genome-wide association studies

27 Since 2005, genome-wide association (GWA) datasets have been largely biased toward sampling Eu28 ropean ancestry individuals, and recent studies have shown that GWA results estimated from European 29 ancestry individuals apply heterogeneously in non-European ancestry individuals. Here, we argue that 30 enrichment analyses which aggregate SNP-level association statistics at multiple genomic scales—to genes 31 and pathways—have been overlooked and can generate biologically interpretable hypotheses regarding 32 the genetic basis of complex trait architecture. We illustrate examples of the insights generated by enrich33 ment analyses while studying 25 continuous traits assayed in 566,786 individuals from seven self-identified 34 human ancestries in the UK Biobank and the Biobank Japan, as well as 44,348 admixed individuals from 35