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; Andrew D Johnson; NHLBI Trans-Omics for Precision (TOPMed) Consortium

doi:10.1038/s41467-021-23470-9

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Genome sequencing unveils a regulatory landscape of platelet reactivity

Journal article

Open access

Peer reviewed

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, …

Nature communications, Vol.12(1), pp.3626-3626

06/15/2021

DOI: 10.1038/s41467-021-23470-9

PMCID: PMC8206369

PMID: 34131117

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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.

Phenotype

Base Sequence

Blood Platelets - metabolism

Chromosome Mapping

Genome-Wide Association Study

GTP-Binding Proteins

HEK293 Cells

Humans

K562 Cells

Platelet Aggregation

Platelet Function Tests

Polymorphism, Single Nucleotide

Quantitative Trait Loci

Receptors, Cell Surface - genetics

RGS Proteins - genetics

RGS Proteins - metabolism

Thrombosis - genetics

Whole Genome Sequencing

Details

Title: Subtitle: Genome sequencing unveils a regulatory landscape of platelet reactivity
Creators: Ali R Keramati - Johns Hopkins University School of Medicine
Ming-Huei Chen - National Heart Lung and Blood Institute
Benjamin A T Rodriguez - Valo Health, Boston, MA, USA
Lisa R Yanek - Johns Hopkins University School of Medicine
Arunoday Bhan - Boston Children's Hospital
Brady J Gaynor - University of Maryland Medical Center
Kathleen Ryan - University of Maryland Medical Center
Jennifer A Brody - University of Washington
Xue Zhong - Vanderbilt University Medical Center
Qiang Wei - Vanderbilt University
Kai Kammers - Sidney Kimmel Comprehensive Cancer Center
Kanika Kanchan - Johns Hopkins Medicine
Kruthika Iyer - Johns Hopkins Medicine
Madeline H Kowalski - University of North Carolina at Chapel Hill
Achilleas N Pitsillides - Boston University
L Adrienne Cupples - Boston University
Bingshan Li - Vanderbilt University
Thorsten M Schlaeger - Boston Children's Hospital
Alan R Shuldiner - University of Maryland, Baltimore
Jeffrey R O'Connell - University of Maryland, Baltimore
Ingo Ruczinski - Johns Hopkins University
Braxton D Mitchell - University of Maryland, Baltimore
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, Baltimore
Rasika A Mathias - Johns Hopkins Medicine
Andrew D Johnson - Framingham Heart Study
NHLBI Trans-Omics for Precision (TOPMed) Consortium
Contributors: Karin Hoth (Contributor) - University of Iowa, Psychiatry
Resource Type: Journal article
Publication Details: Nature communications, Vol.12(1), pp.3626-3626
DOI: 10.1038/s41467-021-23470-9
PMID: 34131117
PMCID: PMC8206369
NLM abbreviation: Nat Commun
ISSN: 2041-1723
eISSN: 2041-1723
Grant note: U01 GM074518 / NIGMS NIH HHS Medical Research Council HHSN268201500014C / NHLBI NIH HHS R01 HL118356 / NHLBI NIH HHS U01 HL105198 / NHLBI NIH HHS R01 HL120393 / NHLBI NIH HHS R01 HL121007 / NHLBI NIH HHS N02 HL64278 / NHLBI NIH HHS R01 HL087698 / NHLBI NIH HHS K01 AG059898 / NIA NIH HHS HHSN268201500001I / NHLBI NIH HHS U54 DK110805 / NIDDK NIH HHS HHSN268201500001C / NHLBI NIH HHS P30 DK072488 / NIDDK NIH HHS N01HC25195 / NHLBI NIH HHS R01 HL141944 / NHLBI NIH HHS M01 RR000052 / NCRR NIH HHS R01 HL137922 / NHLBI NIH HHS U01 HL072518 / NHLBI NIH HHS R01 HL117626 / NHLBI NIH HHS U01 HG009086 / NHGRI NIH HHS R01 HL112064 / NHLBI NIH HHS T32 HL066987 / NHLBI NIH HHS
Language: English
Date published: 06/15/2021
Academic Unit: Psychiatry; Iowa Neuroscience Institute
Record Identifier: 9984293754502771

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