Key result
Whole genome sequencing identified 16 independent loci associated with platelet aggregation, including novel loci RGS18 and SVEP1, and rare variants in a PEAR1 super-enhancer.
Why the study?
Exaggerated platelet aggregation at vascular injury underlies thrombotic diseases, motivating whole genome sequencing to uncover the genetic determinants of platelet aggregation.
Observational (n=3,855)
Yes
Whole genome sequencing identified novel genetic loci, including RGS18 and SVEP1, that regulate platelet reactivity, providing new insights into the genetic basis of arterial thrombosis.
Exaggerated platelet aggregation at the site of vascular injury is the underlying pathophysiology of thrombotic diseases. Here, we conduct the largest whole genome sequencing (WGS) effort to uncover the genetic determinants of platelet aggregation. Leveraging 3,855 NHLBI Trans-Omics for Precision Medicine (TOPMed) individuals deeply phenotyped for platelet aggregation, we identify 18 loci using single-variant approaches. This includes the novel RGS18 locus encoding a myeloerythroid lineage-specific regulator of G-protein signaling that co-localizes with eQTL signatures for RGS18 expression in platelets. A gene-based approach focusing on deleterious coding variants identifies the SVEP1 gene, previously shown to be associated with coronary artery disease, as a novel determinant of platelet aggregation. Finally, in an integrative approach leveraging epigenetic data on megakaryocytes, we find strong association between rare variants mapping to a super enhancer region for PEAR1. This is a novel finding implicating the importance of rare variants with regulatory potential in a previously documented GWAS-identified locus.
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Keramati et al. (2019) conducted an observational in Platelet aggregation (n=3,855). Genetic variants (Whole genome sequencing) vs. Reference alleles was evaluated on Platelet aggregation in response to ADP, epinephrine, or collagen (p=<5x10-8). Whole genome sequencing identified 16 independent loci associated with platelet aggregation, including novel loci RGS18 and SVEP1, and rare variants in a PEAR1 super-enhancer.
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