A signature of platelet reactivity in CBC scattergrams reveals genetic predictors of thrombotic disease risk

Hippolyte Verdier; Patrick Thomas; Joana Batista; Carly Kempster; Harriet McKinney; Nicholas Gleadall; John Danesh; Andrew Mumford; Johan W.M. Heemskerk; Willem H. Ouwehand; Kate Downes; William J. Astle; Ernest Turro

doi:10.1182/blood.2023021100

A signature of platelet reactivity in CBC scattergrams reveals genetic predictors of thrombotic disease risk

Hippolyte Verdier, Patrick Thomas, Joana Batista, Carly Kempster, Harriet McKinney, Nicholas Gleadall, John Danesh, Andrew Mumford, Johan W.M. Heemskerk, Willem H. Ouwehand, Kate Downes, William J. Astle, Ernest Turro

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

5 Scopus citations

Abstract

Genetic studies of platelet reactivity (PR) phenotypes may identify novel antiplatelet drug targets. However, such studies have been limited by small sample sizes (n < 5000) because of the complexity of measuring PR. We trained a model to predict PR from complete blood count (CBC) scattergrams. A genome-wide association study of this phenotype in 29 806 blood donors identified 21 distinct associations implicating 20 genes, of which 6 have been identified previously. The effect size estimates were significantly correlated with estimates from a study of flow cytometry–measured PR and a study of a phenotype of in vitro thrombus formation. A genetic score of PR built from the 21 variants was associated with the incidence rates of myocardial infarction and pulmonary embolism. Mendelian randomization analyses showed that PR was causally associated with the risks of coronary artery disease, stroke, and venous thromboembolism. Our approach provides a blueprint for using phenotype imputation to study the determinants of hard-to-measure but biologically important hematological traits.

Original language	English
Pages (from-to)	1895-1908
Number of pages	14
Journal	Blood
Volume	142
Issue number	22
DOIs	https://doi.org/10.1182/blood.2023021100
State	Published - 30 Nov 2023

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@article{7c89528aa70a4165834fcc32524e3f1c,

title = "A signature of platelet reactivity in CBC scattergrams reveals genetic predictors of thrombotic disease risk",

abstract = "Genetic studies of platelet reactivity (PR) phenotypes may identify novel antiplatelet drug targets. However, such studies have been limited by small sample sizes (n < 5000) because of the complexity of measuring PR. We trained a model to predict PR from complete blood count (CBC) scattergrams. A genome-wide association study of this phenotype in 29 806 blood donors identified 21 distinct associations implicating 20 genes, of which 6 have been identified previously. The effect size estimates were significantly correlated with estimates from a study of flow cytometry–measured PR and a study of a phenotype of in vitro thrombus formation. A genetic score of PR built from the 21 variants was associated with the incidence rates of myocardial infarction and pulmonary embolism. Mendelian randomization analyses showed that PR was causally associated with the risks of coronary artery disease, stroke, and venous thromboembolism. Our approach provides a blueprint for using phenotype imputation to study the determinants of hard-to-measure but biologically important hematological traits.",

author = "Hippolyte Verdier and Patrick Thomas and Joana Batista and Carly Kempster and Harriet McKinney and Nicholas Gleadall and John Danesh and Andrew Mumford and Heemskerk, \{Johan W.M.\} and Ouwehand, \{Willem H.\} and Kate Downes and Astle, \{William J.\} and Ernest Turro",

note = "Publisher Copyright: {\textcopyright} 2023 The American Society of Hematology",

year = "2023",

month = nov,

day = "30",

doi = "10.1182/blood.2023021100",

language = "English",

volume = "142",

pages = "1895--1908",

journal = "Blood",

issn = "0006-4971",

publisher = "Elsevier B.V.",

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T1 - A signature of platelet reactivity in CBC scattergrams reveals genetic predictors of thrombotic disease risk

AU - Verdier, Hippolyte

AU - Thomas, Patrick

AU - Batista, Joana

AU - Kempster, Carly

AU - McKinney, Harriet

AU - Gleadall, Nicholas

AU - Danesh, John

AU - Mumford, Andrew

AU - Heemskerk, Johan W.M.

AU - Ouwehand, Willem H.

AU - Downes, Kate

AU - Astle, William J.

AU - Turro, Ernest

PY - 2023/11/30

Y1 - 2023/11/30

N2 - Genetic studies of platelet reactivity (PR) phenotypes may identify novel antiplatelet drug targets. However, such studies have been limited by small sample sizes (n < 5000) because of the complexity of measuring PR. We trained a model to predict PR from complete blood count (CBC) scattergrams. A genome-wide association study of this phenotype in 29 806 blood donors identified 21 distinct associations implicating 20 genes, of which 6 have been identified previously. The effect size estimates were significantly correlated with estimates from a study of flow cytometry–measured PR and a study of a phenotype of in vitro thrombus formation. A genetic score of PR built from the 21 variants was associated with the incidence rates of myocardial infarction and pulmonary embolism. Mendelian randomization analyses showed that PR was causally associated with the risks of coronary artery disease, stroke, and venous thromboembolism. Our approach provides a blueprint for using phenotype imputation to study the determinants of hard-to-measure but biologically important hematological traits.

AB - Genetic studies of platelet reactivity (PR) phenotypes may identify novel antiplatelet drug targets. However, such studies have been limited by small sample sizes (n < 5000) because of the complexity of measuring PR. We trained a model to predict PR from complete blood count (CBC) scattergrams. A genome-wide association study of this phenotype in 29 806 blood donors identified 21 distinct associations implicating 20 genes, of which 6 have been identified previously. The effect size estimates were significantly correlated with estimates from a study of flow cytometry–measured PR and a study of a phenotype of in vitro thrombus formation. A genetic score of PR built from the 21 variants was associated with the incidence rates of myocardial infarction and pulmonary embolism. Mendelian randomization analyses showed that PR was causally associated with the risks of coronary artery disease, stroke, and venous thromboembolism. Our approach provides a blueprint for using phenotype imputation to study the determinants of hard-to-measure but biologically important hematological traits.

UR - https://www.scopus.com/pages/publications/85175339380

U2 - 10.1182/blood.2023021100

DO - 10.1182/blood.2023021100

M3 - Article

C2 - 37647652

AN - SCOPUS:85175339380

SN - 0006-4971

VL - 142

SP - 1895

EP - 1908

JO - Blood

JF - Blood

IS - 22

ER -

A signature of platelet reactivity in CBC scattergrams reveals genetic predictors of thrombotic disease risk

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