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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 the UK Biobank ( N  = 441 331). Testing 843 phenotypes, we identified 82 independent genomic regions mapping variants showing genome-wide significant (GWS) associations ( P  &lt; 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 and (ii) loci with a GWS association in one ancestry group and an experiment-wide significant discordant effect ( P  &lt; 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 the allele frequency (Δ AF ) and linkage disequilibrium regulome tagging (Δ LD ) between European populations and the other ancestries. Within loci with concordant effects, the degree of heterogeneity was associated with European–Middle Eastern Δ AF  ( P  = 9.04 × 10 −6 ) and Δ LD  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, Δ AF  and Δ LD  of European populations with respect to African and Central/South Asian ancestries were associated with the degree of heterogeneity (Δ AF :  P  = 7.69 × 10 −3  and  P  = 5.31 × 10 −3 , Δ LD :  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 owing to large allele frequency and LD variation among worldwide populations.

human molecular genetics

Cross-ancestry genome-wide association studies identified heterogeneous loci associated with differences of allele frequency and regulome tagging between participants of European descent and other ancestry groups from the UK Biobank