Genome sequencing unveils a regulatory landscape of platelet reactivity

Ali R. Keramati, Ming-Huei Chen, Benjamin A. T. Rodriguez, Lisa R. Yanek, Arunoday Bhan, Brady J. Gaynor, Kathleen Ryan, Jennifer A. Brody, Xue Zhong, Qiang Wei, Kai Kammers, Kanika Kanchan, Kruthika Iyer, Madeline H. Kowalski, Achilleas N. Pitsillides, L. Adrienne Cupples, Bingshan Li, Thorsten M. Schlaeger, Alan R. Shuldiner, Jeffrey R. O’Connell, Ingo Ruczinski, Braxton D. Mitchell, Nauder Faraday, Margaret A. Taub, Lewis C. Becker, Joshua P. Lewis (), Rasika A. Mathias () and Andrew D. Johnson ()
Additional contact information
Ali R. Keramati: Johns Hopkins University School of Medicine
Ming-Huei Chen: Lung and Blood Institute
Benjamin A. T. Rodriguez: Lung and Blood Institute
Lisa R. Yanek: Johns Hopkins University School of Medicine
Arunoday Bhan: Boston Children’s Hospital
Brady J. Gaynor: University of Maryland School of Medicine
Kathleen Ryan: University of Maryland School of Medicine
Jennifer A. Brody: University of Washington School of Medicine
Xue Zhong: Vanderbilt University Medical Center
Qiang Wei: Vanderbilt University
Kai Kammers: Johns Hopkins University School of Medicine
Kanika Kanchan: Johns Hopkins University School of Medicine
Kruthika Iyer: Johns Hopkins University School of Medicine
Madeline H. Kowalski: University of North Carolina
Achilleas N. Pitsillides: The Framingham Heart Study
L. Adrienne Cupples: The Framingham Heart Study
Bingshan Li: Vanderbilt University
Thorsten M. Schlaeger: Boston Children’s Hospital
Alan R. Shuldiner: University of Maryland School of Medicine, Baltimore
Jeffrey R. O’Connell: University of Maryland School of Medicine
Ingo Ruczinski: Johns Hopkins University
Braxton D. Mitchell: University of Maryland School of Medicine
Nauder Faraday: Johns Hopkins University School of Medicine
Margaret A. Taub: Johns Hopkins University
Lewis C. Becker: Johns Hopkins University School of Medicine
Joshua P. Lewis: University of Maryland School of Medicine
Rasika A. Mathias: Johns Hopkins University School of Medicine
Andrew D. Johnson: Lung and Blood Institute

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract Platelet aggregation at the site of atherosclerotic vascular injury is the underlying pathophysiology of myocardial infarction and stroke. To build upon prior GWAS, here we report on 16 loci identified through a whole genome sequencing (WGS) approach in 3,855 NHLBI Trans-Omics for Precision Medicine (TOPMed) participants deeply phenotyped for platelet aggregation. We identify the RGS18 locus, which encodes a myeloerythroid lineage-specific regulator of G-protein signaling that co-localizes with expression quantitative trait loci (eQTL) signatures for RGS18 expression in platelets. Gene-based approaches implicate the SVEP1 gene, a known contributor of coronary artery disease risk. Sentinel variants at RGS18 and PEAR1 are associated with thrombosis risk and increased gastrointestinal bleeding risk, respectively. Our WGS findings add to previously identified GWAS loci, provide insights regarding the mechanism(s) by which genetics may influence cardiovascular disease risk, and underscore the importance of rare variant and regulatory approaches to identifying loci contributing to complex phenotypes.

Date: 2021
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DOI: 10.1038/s41467-021-23470-9

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