Nature communications · 2021
Genome sequencing unveils a regulatory landscape of platelet reactivity.
СтатьяПоддержка NIH: внешняя программаResearch Support, N.I.H., IntramuralПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Keramati Ali R, Chen Ming-Huei, Rodriguez Benjamin A T, 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
Аннотация
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.