Genome sequencing unveils a regulatory landscape of platelet reactivity

doi:10.1038/s41467-021-23470-9

Genome sequencing unveils a regulatory landscape of platelet reactivity

Research output: Contribution to journal › Article › peer-review

40 Scopus citations

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.

Original language	English
Article number	3626
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-23470-9
State	Published - Dec 1 2021

Bibliographical note

Publisher Copyright:
© 2021, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

Funding

Whole genome sequencing (WGS) for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung and Blood Institute (NHLBI). WGS for GeneSTAR (Genetic Study of Atherosclerosis Risk) was performed at Macrogen, Illumina, and the Broad Institute of MIT and Harvard (HHSN268201500014C). WGS for the Old Order Amish (Genetics of Cardiometabolic Health in the Amish) was performed at the Broad Institute of MIT and Harvard (3R01HL121007-01S1). WGS for The Framingham Heart Study (Whole Genome Sequencing and Related Phenotypes in the Framingham Heart Study) was performed at the Broad Institute of MIT and Harvard (HHSN268201500014C). Centralized read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1). Phenotype harmonization, data management, sample-identity QC, and general study coordination, were provided by the TOPMed Data Coordinating Center (3R01HL-120393-02S1). For the Old Order Amish this investigation was supported by National Institutes of Health grants U01 GM074518, U01 HL105198, R01 HL137922, R01 HL121007, and the University of Maryland Mid-Atlantic Nutrition and Obesity Research Center (P30 DK072488). GeneSTAR was supported by the National Institutes of Health/National Heart, Lung, and Blood Institute (U01 HL72518, HL087698, HL112064, HL11006, HL118356) and by a grant from the National Institutes of Health/National Center for Research Resources (M01-RR000052) to the Johns Hopkins General Clinical Research Center. The Framingham Heart Study is conducted and supported by the NHLBI in collaboration with Boston University (Contract No. N01-HC-25195), its contract with Affymetrix, Inc., for genome-wide genotyping services (Contract No. N02-HL-6\u20134278 and Contract No. HHSN268201500001I). MHC, BATC and ADJ were supported by NHLBI Intramural funding. The Caerphilly Prospective study was undertaken by the former MRC Epidemiology Unit (South Wales) and was funded by the Medical Research Council of the UK. The data archive is maintained by the School of Social and Community Medicine, University of Bristol. This study makes use of data generated by the BLUEPRINT Consortium. A full list of the investigators who contributed to the generation of the data is available from www.blueprint-epigenome.eu. Funding for the project was provided by the European Union\u2019s Seventh Framework Programme (FP7/ 2007-2013) under grant agreement no 282510 BLUEPRINT. Additional support came from the National Blood Foundation/American Association of Blood Banks (FP01021164), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK; U54DK110805) and the National Research Service Award (NRSA)\u2019s Joint Program in Transfusion Medicine (T32 4T32HL066987-15 to A.B.). BioVU resource analyses were supported by National Institutes of Health/National Genome Research Institute grant U01HG009086. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services.

Funders	Funder number
Medical Research Council
Johns Hopkins General Clinical Research Center
National Blood Foundation/American Association of Blood Banks	FP01021164
Israel National Road Safety Authority	T32 4T32HL066987-15
Israel National Road Safety Authority
National Center for Research Resources	M01-RR000052
National Center for Research Resources
Seventh Framework Programme	282510
Seventh Framework Programme
National Heart, Lung, and Blood Institute (NHLBI)	U01 HL72518, HL112064, HL11006, HL118356, HL087698
National Heart, Lung, and Blood Institute (NHLBI)
University of Maryland Mid-Atlantic Nutrition and Obesity Research Center	P30 DK072488
National Institutes of Health (NIH)	R01 HL121007, U01 GM074518, U01 HL105198, R01 HL137922
National Institutes of Health (NIH)
Boston University School of Public Health/Boston University Medical Campus	N02-HL-6–4278, N01-HC-25195, HHSN268201500001I
Boston University School of Public Health/Boston University Medical Campus
National Institute of Diabetes and Digestive and Kidney Diseases	U54DK110805
National Institute of Diabetes and Digestive and Kidney Diseases
National Human Genome Research Institute	U01HG009086
National Human Genome Research Institute

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

Access to Document

10.1038/s41467-021-23470-9

Cite this

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title = "Genome sequencing unveils a regulatory landscape of platelet reactivity",

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.",

author = "Keramati, \{Ali R.\} and Chen, \{Ming Huei\} and Rodriguez, \{Benjamin A.T.\} and Yanek, \{Lisa R.\} and Arunoday Bhan and Gaynor, \{Brady J.\} and Kathleen Ryan and Brody, \{Jennifer A.\} and Xue Zhong and Qiang Wei and Namiko Abe and Goncalo Abecasis and Francois Aguet and Christine Albert and Laura Almasy and Alvaro Alonso and Seth Ament and Peter Anderson and Pramod Anugu and Deborah Applebaum-Bowden and Kristin Ardlie and Dan Arking and Arnett, \{Donna K.\} and Allison Ashley-Koch and Stella Aslibekyan and Tim Assimes and Paul Auer and Dimitrios Avramopoulos and Najib Ayas and Adithya Balasubramanian and John Barnard and Kathleen Barnes and Barr, \{R. Graham\} and Emily Barron-Casella and Lucas Barwick and Terri Beaty and Gerald Beck and Diane Becker and Lewis Becker and Rebecca Beer and Amber Beitelshees and Emelia Benjamin and Takis Benos and Marcos Bezerra and Larry Bielak and Joshua Bis and Thomas Blackwell and John Blangero and Eric Boerwinkle and Bowden, \{Donald W.\}",

note = "Publisher Copyright: {\textcopyright} 2021, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.",

year = "2021",

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doi = "10.1038/s41467-021-23470-9",

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AU - Keramati, Ali R.

AU - Chen, Ming Huei

AU - Rodriguez, Benjamin A.T.

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AU - Bhan, Arunoday

AU - Gaynor, Brady J.

AU - Ryan, Kathleen

AU - Brody, Jennifer A.

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AU - Abecasis, Goncalo

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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 - Becker, Lewis

AU - Beer, Rebecca

AU - Beitelshees, Amber

AU - Benjamin, Emelia

AU - Benos, Takis

AU - Bezerra, Marcos

AU - Bielak, Larry

AU - Bis, Joshua

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AU - Blangero, John

AU - Boerwinkle, Eric

AU - Bowden, Donald W.

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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DO - 10.1038/s41467-021-23470-9

M3 - Article

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AN - SCOPUS:85108227070

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3626

ER -

Genome sequencing unveils a regulatory landscape of platelet reactivity

Abstract

Bibliographical note

Funding

UN SDGs

ASJC Scopus subject areas

Access to Document

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Cite this