Discovery of ancestry-specific variants associated with clopidogrel response among Caribbean Hispanics

Figures

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  Fig. 1. Participant Enrollment and Data Selection Process. Flowchart to illustrate the number of cardiovascular (CV) participants who were enrolled in the study protocol from seven different medical facilities across the Commonwealth of Puerto Rico, between January 2018 and June 2020 and the total number of patients with full data considered for the final association analyses.

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  Fig. 2. Genetic admixture in Caribbean Hispanics. A Density plots of the study cohort with green representing Native American (AMR: 103 Native Mesoamerican and South American individuals from the Human Genome Diversity Project/ Centre d’Etude du Polymorphism database (HGDP-CEPH); representing Maya and Pima in Mexico, Colombian in Colombia, Karitiana and Surui in Brazil), purple representing African (YRI: 61 Yoruba in Ibadan, Nigeria from 1KGP), and cyan representing European (IBS: 107 Iberian populations in Spain from 1KGP) ancestries, respectively42,43. There are different proportions of African and European contributions to the overall genetic background of each participant. Native American curve suggests this ancestral component is less variable among participants, but also smaller in terms of global proportion. B The individual proportions of the three parental components in the study cohort (ancestral fractions). Each column represents an individual in the study cohort. C Principal component analysis (PCA) in each participant of the study (PR: Caribbean Hispanics from Puerto Rico, in red color) along with the European (IBS), African (YRI), and Native American (AMR) reference…

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  Fig. 3. Manhattan and QQ plot from traditional GWAS. Manhattan plot representing the association between single nucleotide polymorphisms (SNPs) and Platelet Reactivity Units (PRU) or High on Treatment Platelet Reactivity (HTPR). The x-axis shows the position of each SNP on the chromosome, while the y-axis displays the association (−log10 p-value) between the SNP and the trait of interest. The blue line represents the suggestive level of significance (p = 1·10−6). Threshold for genome-wide significance (p = 5·10−8) not shown. The QQ plot displays the observed p-values of the genome-wide association study (GWAS) summary data on the y-axis, compared to the expected p-values under the null hypothesis of no association on the x-axis. Deviations from the diagonal line indicate departures from the null hypothesis, where points above the line suggest more significant associations than expected, while points below the line suggest fewer significant associations than expected. A The GWAS of PRU using linear regression identified 3 loci (ZNF860 on chromosome 3, DERL3 on chromosome 22, and RGS6 on chromosome 14) to be associated with the changes of PRU value at the suggestive level of significance…

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  Fig. 4. Manhattan plot of LAI adjusted GWAS. After tractor analysis, we used METAL to perform a meta-analysis across all the ancestry to obtain associating results that were adjusted for LAI (A) No variant reached the suggestive significance level in linear regression model local ancestry inference GWAS. B The logistic regression model local ancestry inference GWAS showed one locus on chromosome 10 associated with increased risk of HTPR at the suggestive level of significance (p < 1·10-6).

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  Fig. 5. Region plot of top SNP from LAI logistic GWAS. The colors of the circles refer to linkage disequilibrium (LD) (r2) between top SNP rs12571421 (purple diamond) and nearby SNPs (based on pairwise r2 values from the 1000 Genomes Project reference panel). The blue line and right y-axis show the estimated recombination rate. The x-axis represents the genomic position in chromosome 10 and the left y-axis represents the −log10 p-value of association with HTPR in discovery cohort. Region plot showed CYP2C19*2 variant rs4244285 is high LD with top SNP rs12571421.