Inter-population differences of allele frequency and regulome tagging are associated with the heterogeneity of loci identified by cross-ancestry genome-wide association studies

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 domains may present considerable cross-ancestry heterogeneity due to large allele frequency and LD variation among worldwide populations. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Yale investigators acknowledge support from the National Institutes of Health via R21 DA047527, R21 DC018098, and F32 MH122058. The sources of funding had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was conducted using summary association data generated by previous studies. Owing to the use of previously collected, deidentified, aggregated data, this study did not require institutional review board approval. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data supporting the findings of this study are available within this article and its additional files.