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Genome sequencing unveils a regulatory landscape of platelet reactivity

Author

Listed:
  • Ali R. Keramati

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Ming-Huei Chen

    (Lung and Blood Institute
    The Framingham Heart Study)

  • Benjamin A. T. Rodriguez

    (Lung and Blood Institute
    The Framingham Heart Study
    Valo Health)

  • Lisa R. Yanek

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Arunoday Bhan

    (Boston Children’s Hospital)

  • Brady J. Gaynor

    (University of Maryland School of Medicine
    University of Maryland School of Medicine, Baltimore)

  • Kathleen Ryan

    (University of Maryland School of Medicine
    University of Maryland School of Medicine, Baltimore)

  • 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
    Boston University)

  • L. Adrienne Cupples

    (The Framingham Heart Study
    Boston University)

  • 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
    University of Maryland School of Medicine, Baltimore)

  • Ingo Ruczinski

    (Johns Hopkins University)

  • Braxton D. Mitchell

    (University of Maryland School of Medicine
    University of Maryland School of Medicine, Baltimore)

  • Nauder Faraday

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Margaret A. Taub

    (Johns Hopkins University)

  • Lewis C. Becker

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Joshua P. Lewis

    (University of Maryland School of Medicine
    University of Maryland School of Medicine, Baltimore)

  • Rasika A. Mathias

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Andrew D. Johnson

    (Lung and Blood Institute
    The Framingham Heart Study)

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.

Suggested Citation

  • 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, 2021. "Genome sequencing unveils a regulatory landscape of platelet reactivity," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23470-9
    DOI: 10.1038/s41467-021-23470-9
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    Cited by:

    1. Jared S. Elenbaas & Upasana Pudupakkam & Katrina J. Ashworth & Chul Joo Kang & Ved Patel & Katherine Santana & In-Hyuk Jung & Paul C. Lee & Kendall H. Burks & Junedh M. Amrute & Robert P. Mecham & Car, 2023. "SVEP1 is an endogenous ligand for the orphan receptor PEAR1," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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