LAUSR

To investigate cross-ancestry genetics of complex traits, we conducted a phenome-wide analysis of loci with heterogeneous effects across African, Admixed-American, Central/South Asian, East Asian, European, and Middle Eastern participants of UK Biobank (N = 441 331). Testing 843 phenotypes, we identified 82 independent genomic regions mapping variants showing genome-wide significant (GWS) associations (P < 5 × 10-8) in the trans-ancestry meta-analysis and GWS heterogeneity among the ancestry-specific effects. These included: i) loci with GWS association in one ancestry and concordant but heterogeneous effects among the other ancestries; ii) loci with a GWS association in one ancestry group and an experiment-wide significant discordant effect (P < 6.1 × 10-4) in at least another ancestry. Since the trans-ancestry GWS associations were mostly driven by the European-ancestry sample size, we investigated the differences of allele frequency (ΔAF) and linkage-disequilibrium regulome tagging (ΔLD) between European populations and the other ancestries. Within loci with concordant effects, the degree of heterogeneity was associated with European-Middle Eastern ΔAF (P = 9.04 × 10-6) and ΔLD of European populations with respect to African, Admixed-American, and Central/South Asian groups (P = 8.21 × 10-4, P = 7.17 × 10-4, and P = 2.16 × 10-3, respectively). Within loci with discordant effects, ΔAF and ΔLD of European populations with respect to African and Central/South Asian ancestries was associated with the degree of heterogeneity (ΔAF: P = 7.69 × 10-3 and P = 5.31 × 10-3, ΔLD: P = 0.016 and P = 2.65 × 10-4, respectively). Considering the traits associated with cross-ancestry heterogeneous loci, we observed enrichments for blood biomarkers (P = 5.7 × 10-35) and physical appearance (P = 1.38 × 10-4). This suggests that these specific phenotypic classes may present considerable cross-ancestry heterogeneity due to large allele frequency and LD variation among worldwide populations.