TY - JOUR
T1 - Genome sequencing unveils a regulatory landscape of platelet reactivity
AU - NHLBI Trans-Omics for Precision (TOPMed) Consortium
AU - Keramati, Ali R.
AU - Chen, Ming Huei
AU - Rodriguez, Benjamin A.T.
AU - Yanek, Lisa R.
AU - Bhan, Arunoday
AU - Gaynor, Brady J.
AU - Ryan, Kathleen
AU - Brody, Jennifer A.
AU - Zhong, Xue
AU - Wei, Qiang
AU - Abe, Namiko
AU - Abecasis, Goncalo
AU - Aguet, Francois
AU - Albert, Christine
AU - Almasy, Laura
AU - Alonso, Alvaro
AU - Ament, Seth
AU - Anderson, Peter
AU - Anugu, Pramod
AU - Applebaum-Bowden, Deborah
AU - Ardlie, Kristin
AU - Arking, Dan
AU - Arnett, Donna K.
AU - Ashley-Koch, Allison
AU - Aslibekyan, Stella
AU - Assimes, Tim
AU - Auer, Paul
AU - Avramopoulos, Dimitrios
AU - Ayas, Najib
AU - Balasubramanian, Adithya
AU - Barnard, John
AU - Barnes, Kathleen
AU - Barr, R. Graham
AU - Barron-Casella, Emily
AU - Barwick, Lucas
AU - Beaty, Terri
AU - Beck, Gerald
AU - Becker, Diane
AU - Casella, James
AU - Mathias, Rasika
AU - Naik, Rakhi
AU - Post, Wendy
AU - Becker, Julia Powers
AU - Salzberg, Steven
AU - Taub, Margaret
AU - Vaidya, Dhananjay
AU - Kammers, Kai
AU - Ruczinski, Ingo
AU - Faraday, Nauder
AU - Becker, Lewis C.
N1 - Publisher Copyright:
© 2021, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-021-23470-9
DO - 10.1038/s41467-021-23470-9
M3 - Article
C2 - 34131117
AN - SCOPUS:85108227070
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 3626
ER -