Genome-wide association study of platelet aggregation in African Americans

Abstract

Background: We have previously shown that platelet aggregation has higher heritability in African Americans than European Americans. However, a genome-wide association study (GWAS) of platelet aggregation in African Americans has not been reported. We measured platelet aggregation in response to arachidonic acid, ADP, collagen, or epinephrine by optical aggregometry. The discovery cohort was 825 African Americans from the GeneSTAR study. Two replication cohorts were used: 119 African Americans from the Platelet Genes and Physiology Study and 1221 European Americans from GeneSTAR. Genotyping was conducted with Illumina 1 M arrays. For each cohort, age- and sex-adjusted linear mixed models were used to test for association between each SNP and each phenotype under an additive model.

Results: Six SNPs were significantly associated with platelet aggregation (P<5×10(-8)) in the discovery sample. Of these, three SNPs in three different loci were confirmed: 1) rs12041331, in PEAR1 (platelet endothelial aggregation receptor 1), replicated in both African and European Americans for collagen- and epinephrine-induced aggregation, and in European Americans for ADP-induced aggregation; 2) rs11202221, in BMPR1A (bone morphogenetic protein receptor type1A), replicated in African Americans for ADP-induced aggregation; and 3) rs6566765 replicated in European Americans for ADP-induced aggregation. The rs11202221 and rs6566765 associations with agonist-induced platelet aggregation are novel.

Conclusions: In this first GWAS of agonist-induced platelet aggregation in African Americans, we discovered and replicated, novel associations of two variants with ADP-induced aggregation, and confirmed the association of a PEAR1 variant with multi-agonist-induced aggregation. Further study of these genes may provide novel insights into platelet biology.

Fig. 1

Manhattan plot of the genome-wide association results of agonist-mediated platelet aggregation. The y-axis represents the negative logarithm (base 10) of p-values and the x-axis represents chromosomes with positions of genetic variants. The horizontal red line represents the genome-wide significance threshold. Results of arachidonic acid-mediated platelet aggregation are not shown here as no genetic variant crossed genome-wide significance threshold

Fig. 2

Upper half: Results of association between genetic variants in BMPR1A gene and ADP 2 μM in the GeneSTAR African American cohort and PGAP with the vertical bar highlighting the lead genetic variant in the region. The y-axis represents the negative logarithm (base 10) of p-values and the x-axis represent the base-pair position of genetic variants on chromosome 10. Lower half: Linkage disequilibrium plot of the BMPR1A region in the GeneSTAR African American cohort. Lead genetic variant in the region is highlighted with a blue background