Multi-trait GWAS reveals divergent local and polygenic architecture of cardiovascular traits across African and European ancestries in the UK Biobank.

Figures

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  Fig. 1. Cardiovascular parameters and anthropometric correlations in Africans and Europeans. Comparison of the cardiovascular function parameter in Africans and Europeans for (a) diastolic blood pressure, (b) systolic blood pressure, (c) pulse rate, and (d) maximum heart rate during fitness test. The boxplots indicate the distribution of each measurement among Africans and Europeans. The p-values shown for each comparison were calculated from Welch’s t-test. On each box, the central mark indicates the median, and the left and right edges of the box indicate the 25th and 75th percentiles, respectively. The whiskers extend to the most extreme data points not considered outliers, and the outliers are plotted individually using the '+' symbol. To make the visualisation clearer, the filled circle mark showing the distribution only include 1000 randomly sampled point from the entire samples size of each group. (e) Correlation between SBP, DBP, pulse rate, and MHR with other anthropometric measurements in Africans and Europeans. f Error bars show the DBP variation across BMI percentiles among Africans and Europeans. The middle point indicates the mean DBP, and the error bars indicate the…

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  Fig. 2. Manhattan plots of genetic variants associated with cardiovascular traits in European and African populations. The plots represent the results of MTAG analysis using JASS, depicting genome-wide significant associations with cardiovascular traits, including diastolic blood pressure (DBP), systolic blood pressure (SBP), pulse rate, and max heart rate (MHR) across each chromosome for (a) European (EUR) and (b) African (AFR) populations.

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  Fig. 3. Comparison of Beta Estimates for Top 200 Cardiovascular Trait-Associated Variants. The 200 most significant variants associated with cardiovascular traits in (a) African and (b) European populations. The y-axis illustrates beta estimates and associated errors derived from MTAG analyses, estimated from the z-score output of JASS. The central point of each error bar represents the beta estimate, while the whiskers demonstrate the associated standard error. The markers are coloured differently by ethnicity. Panels (b, d) show the corresponding association strengths (−log₁₀(P)) for the same sets of variants. In all panels, green symbols represent estimates from the European-ancestry cohort and orange/red symbols represent estimates from the African-ancestry cohort. Variants are ranked by their MTAG P-value within the focal ancestry group. Effect sizes (β) and standard errors were derived from MTAG summary statistics (z-score output of JASS). In panels (a, b), error bars represent ± 1 standard error of the beta estimate derived from MTAG analysis. n = 200 variants shown per panel, selected as the most significant in each focal ancestry. European cohort: n = 396,670 biologically…

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  Fig. 4. Ancestry-specific landscape of local genetic correlations for cardiovascular traits. a Equivalent plot for the EUR ancestry sample. Each point represents a genomic locus, plotted by its chromosomal position (x-axis). The y-axis shows the significance of the local genetic correlation for the most significant trait pair within that locus, expressed as −log10(P−value). The dashed horizontal line indicates the threshold for significance after correcting for multiple testing (FDR q < 0.05). Loci containing a genome-wide significant lead SNP from our MTAG analysis (identified via FUMA) are highlighted to distinguish them from other regions. The heatmaps quantifying the number of genomic loci with significant pleiotropic effects shared between pairs of four cardiovascular traits. b Results from the AFR ancestry sample. c Results from the EUR ancestry sample. Each cell in the matrix shows the total count of loci where a significant local genetic correlation (FDR q < 0.05) was detected between the corresponding pair of traits. The colour intensity corresponds to the number of shared significant loci, as indicated by the scale bar.

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  Fig. 5. Regional Association Plots Highlighting Novel and Previously Identified MTAG Loci Associated with Cardiovascular Traits in African Population. The lead SNPs (a) rs56195233 and (b) rs75484900 represent novel findings, while the lead SNPs (c) rs9388010 and (d) rs12568839 have been previously linked to cardiovascular traits. Genes within the chromosomal loci are depicted in the lower panel. The filled circles indicate the position of the SNPs across the region on the x-axis and the negative logarithm of the association p-value on the y-axis. The lead SNP is highlighted in purple, with other SNPs within the locus coloured based on their linkage disequilibrium correlation value (r2) with the lead SNP, utilizing the African HapMap haplotype from the 1000 Genomes Project.

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  Fig. 6. Regional Association Plots Highlighting Novel and Previously Identified MTAG Loci Associated with Cardiovascular Traits in European Population. Regional association plots for MTAG loci significantly associated with cardiovascular traits in the African population. The lead SNPs (a) rs4811602 and (b) rs11153730 represent novel findings, while the lead SNPs (c) rs9320841 and (d) rs34732995 have been previously linked to cardiovascular traits. Genes within the chromosomal loci are depicted in the lower panel. The filled circles indicate the position of the SNPs across the region on the x-axis and the negative logarithm of the association p-value on the y-axis. The lead SNP is highlighted in purple, with other SNPs within the locus coloured based on their linkage disequilibrium correlation value (r2) with the lead SNP, utilizing the European HapMap haplotype from the 1000 Genomes Project.

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  Fig. 7. Functional Annotation of SNPs in AFR and EUR Populations. a African (AFR) population SNP annotations with corresponding proportions shown in the bar graph and pie chart. The bar graph indicates the proportion of SNPs in various genomic regions, with asterisks denoting significance levels: ***p < 0.001, **p < 0.01, *p < 0.05. The pie chart shows the percentage distribution of SNPs across intronic, intergenic, and ncRNA-intronic regions. b European (EUR) population SNP annotations, presented in the same format as the AFR population. The significance levels are marked similarly on the bar graph, and the pie chart reflects the distribution within intronic, intergenic, and ncRNA-intronic regions. The heat map legend on the right side represents the -log2(Enrichment) value of SNPs in each annotation category, with 1 indicating the highest level of enrichment.

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  Fig. 8. Functional enrichment analyses for African and European populations. Bar plots illustrating gene enrichment results based on MTAG analysis-derived SNPs mapped using FUMA. Functional enrichment analyses were conducted with Enrichr and included (a) Gene Ontology (GO) Biological Processes, (b) MGI Mammalian Phenotypes, (c) PhenGenI disease associations, and (d) GWAS Catalog terms derived from the UK Biobank. Comprehensive details are available in Supplementary Data 5.