Abstract 2072: Multiple Platelet Aggregation Genes Are Identified by Genome-wide Association Meta-analyses
Platelet aggregation plays an important role in arterial thrombosis. While a few candidate gene polymorphisms have been previously associated with platelet aggregation, a genome-wide association study (GWAS) has not been reported. We hypothesized that meta-analysis of results from multiple GWAS would discover new genes contributing to aggregation. In two separate GWAS conducted in white participants, the Framingham Heart Study (FHS) Offspring cohort and GeneSTAR (GS), platelet rich plasma (PRP) was isolated from fasting blood samples. Subjects with CAD or anti-coagulant or anti-platelet medication were excluded. PRP samples were treated with varying doses of agonists (collagen, ADP, epinephrine) and lag time, biphasic responses and maximal aggregation were measured. Genotyping was conducted with Affymetrix 500K + 50K MIPs arrays (FHS) and Illumina 1M arrays (GS). After genotyping QC, both cohorts used MACH software to impute 2.54 million common SNPs based on the HapMap. The imputed SNP dosages were used in GWA analyses adjusting for age and sex. Subsequent meta-analyses were conducted by combining effects from both cohorts. Final sample sizes varied with agonist and concentration, with the maximum in meta-analyses being 2,754 for FHS and 1,109 for GS. Additional replication was assessed by SNPs genotyped in GS black samples (up to n=840). Ten distinct loci were associated with platelet aggregation phenotypes at a genome-wide significance level (5×10−8) in the meta-analyses with evidence for association in both cohorts, including 4 loci for ADP, 5 loci for epinephrine, and 2 loci for collagen. Findings included loci containing notable genes: PEAR1 (1q23.1, p=4.1×10−12), ADRA2A (10q25.2, p=1.2×10−10), GP6 (19q13.42, p=4.4×10−10) and IRAG (11p15, p=3.2×10−8). The minor alleles of SNPs in PEAR1 and IRAG showed association with increased aggregation to epinephrine and ADP. The findings for PEAR1, ADRA2A, GP6 and IRAG replicated in black samples. By combining two GWAS we identified and replicated strong associations with platelet aggregation, including newly discovered loci. These findings may have important clinical implications particularly for thrombosis and anti-platelet and anti-coagulant therapy.