101. Genome Sequencing Unveils a New Regulatory Landscape of Platelet Reactivity
- Author
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Jeffrey R. O'Connell, L. Adrienne Cupples, Alan R. Shuldiner, Braxton D. Mitchell, Ali R. Keramati, Lisa R. Yanek, Lewis C. Becker, Brady Gaynor, Kanika Kanchan, Achilleas N. Pitsillides, Joshua P. Lewis, Ming-Huei Chen, Kai Kammers, Nauder Faraday, Rasika A. Mathias, Kruthika R. Iyer, Madeline H. Kowalski, Benjamin Rodriguez, Jennifer A. Brody, Margaret A. Taub, Andrew D. Johnson, Nhlbi TOPMed Hematology, and Kathleen A. Ryan
- Subjects
Whole genome sequencing ,0303 health sciences ,Regulator ,Locus (genetics) ,Computational biology ,030204 cardiovascular system & hematology ,Biology ,DNA sequencing ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,Super-enhancer ,Expression quantitative trait loci ,Epigenetics ,Gene ,030304 developmental biology - Abstract
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.
- Published
- 2019
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