RT Journal Article
SR Electronic
T1 Genome Sequencing Unveils a New Regulatory Landscape of Platelet Reactivity
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 621565
DO 10.1101/621565
A1 Ali R. Keramati
A1 Ming-Huei Chen
A1 Benjamin A.T. Rodriguez
A1 Lisa R. Yanek
A1 Brady J. Gaynor
A1 Kathleen Ryan
A1 Jennifer A. Brody
A1 NHLBI Trans-Omics for Precision (TOPMed) Consortium
A1 NHLBI TOPMed Hematology and Hemostasis Working Group
A1 Kai Kammers
A1 Kanika Kanchan
A1 Kruthika Iyer
A1 Madeline H. Kowalski
A1 Achilleas N. Pitsillides
A1 L. Adrienne Cupples
A1 Alan R. Shuldiner
A1 Jeffrey R. O’Connell
A1 Braxton D. Mitchell
A1 Nauder Faraday
A1 Margaret A. Taub
A1 Lewis C. Becker
A1 Joshua P. Lewis
A1 Rasika A. Mathias
A1 Andrew D. Johnson
YR 2019
UL http://biorxiv.org/content/early/2019/05/16/621565.abstract
AB 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.