Genome sequencing unveils a regulatory landscape of platelet reactivity

NHLBI Trans-Omics for Precision (TOPMed) Consortium

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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.

Original languageEnglish (US)
Article number3626
JournalNature communications
Volume12
Issue number1
DOIs
StatePublished - Dec 2021

Bibliographical note

Funding Information:
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-6–4278 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’s 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)’s 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.

Funding Information:
Open Access funding provided by the National Institutes of Health (NIH).

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

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