Genome sequencing unveils a regulatory landscape of platelet reactivity

Autor: Keramati, Ali R, Chen, Ming-Huei, Rodriguez, Benjamin AT, Yanek, Lisa R, Bhan, Arunoday, Gaynor, Brady J, Ryan, Kathleen, Brody, Jennifer A, Zhong, Xue, Wei, Qiang, NHLBI Trans-Omics for Precision (TOPMed) Consortium, Kammers, Kai, Kanchan, Kanika, Iyer, Kruthika, Kowalski, Madeline H, Pitsillides, Achilleas N, Cupples, L Adrienne, Li, Bingshan, Schlaeger, Thorsten M, Shuldiner, Alan R, O'Connell, Jeffrey R, Ruczinski, Ingo, Mitchell, Braxton D, Faraday, Nauder, Taub, Margaret A, Becker, Lewis C, Lewis, Joshua P, Mathias, Rasika A, Johnson, Andrew D
Rok vydání: 2021
Předmět:
0301 basic medicine
Platelet Aggregation
General Physics and Astronomy
Genome-wide association study
030204 cardiovascular system & hematology
Cardiovascular
Genome-wide association studies
0302 clinical medicine
Receptors
2.1 Biological and endogenous factors
Aetiology
Genetics
Multidisciplinary
Chromosome Mapping
Hematology
Single Nucleotide
Phenotype
Heart Disease
Blood
Cell Surface
Biotechnology
Platelets
Blood Platelets
Quantitative trait loci
Platelet Function Tests
Science
Quantitative Trait Loci
Receptors
Cell Surface
Locus (genetics)
Quantitative trait locus
Biology
Polymorphism
Single Nucleotide
Article
General Biochemistry
Genetics and Molecular Biology
DNA sequencing
03 medical and health sciences
Clinical Research
GTP-Binding Proteins
Humans
Polymorphism
Gene
Heart Disease - Coronary Heart Disease
Whole genome sequencing
Base Sequence
Whole Genome Sequencing
Prevention
Human Genome
Thrombosis
Cardiovascular genetics
NHLBI Trans-Omics for Precision (TOPMed) Consortium
General Chemistry
Atherosclerosis
Coagulation system
Good Health and Well Being
HEK293 Cells
030104 developmental biology
Expression quantitative trait loci
K562 Cells
RGS Proteins
Genome-Wide Association Study
Zdroj: Nature communications, vol 12, iss 1
Nature Communications
Nature Communications, Vol 12, Iss 1, Pp 1-13 (2021)
ISSN: 2041-1723
DOI: 10.1038/s41467-021-23470-9
Popis: 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.
Platelet aggregation is associated with myocardial infarction and stroke. Here, the authors have conducted a whole genome sequencing association study on platelet aggregation, discovering a locus in RGS18, where enhancer assays suggest an effect on activity of haematopoeitic lineage transcription factors.
Databáze: OpenAIRE
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