Abstract
Genetic studies of platelet reactivity (PR) phenotypes may identify novel antiplatelet drug targets. However, discoveries have been limited by small sample sizes (n<5,000) due to the complexity of measuring PR. We trained a model to predict PR from complete blood count (CBC) scattergrams. A GWAS of this phenotype in 29,806 blood donors identified 21 distinct associations implicating 20 genes, of which six 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 myocardial infarction and pulmonary embolism. Mendelian randomisation analyses showed PR to be causally associated with the risks of coronary artery disease, stroke and venous thromboembolism. Our approach provides a blueprint for employing phenotype imputation to study the determinants of hard-to-measure but biologically important haematological traits.
| Original language | English |
|---|---|
| Pages (from-to) | 1895-1908 |
| Number of pages | 14 |
| Journal | Blood |
| Volume | 142 |
| Issue number | 22 |
| Early online date | 30 Aug 2023 |
| DOIs | |
| Publication status | Published - 30 Nov 2023 |
Bibliographical note
Funding Information:The authors are grateful to Stephen Garner for generating part of the Cambridge PFC FC data set and for his invaluable advice on the operation of Sysmex hematology analyzers. The authors thank Jarob Saker and Joachim Linssen of Sysmex Europe for the invaluable technical assistance and advice. The authors gratefully acknowledge the participation of all UK Biobank, NIHR Cambridge BioResource, and INTERVAL volunteers. Participants in the INTERVAL randomized controlled trial were recruited through the active collaboration of NHS Blood and Transplant England, which supported field work and other elements of the trial. A complete list of the investigators of and contributors to the INTERVAL trial is provided in a previous publication.16, This research has been conducted using the UK Biobank resource under application number 13745. The authors are grateful to the Lowy Foundation USA for supporting this work. The authors thank the members of the Cambridge BioResource Scientific Advisory Board and Management Committee for supporting our study and the NIHR Cambridge Biomedical Research Centre for funding (RG64219). DNA extraction and genotyping were cofunded by the National Institute for Health and Care Research (NIHR), the NIHR BioResource, and the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The academic coordinating centre for INTERVAL was supported by core funding from the NIHR Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014-10024), the NIHR Blood and Transplant Research Unit in Donor Health and Behaviour (NIHR203337), the UK Medical Research Council (MR/L003120/1), the British Heart Foundation (SP/09/002, RG/13/13/30194, and RG/18/13/33946) and the NIHR Cambridge BRC (BRC-1215-20014 and NIHR203312). W.J.A. is supported financially by NHS Blood and Transplant. The views expressed are those of the authors and not necessarily those of the NIHR, National Health Service Blood and Transplant, or the Department of Health and Social Care. Contribution: H.V. conducted all analyses and wrote the manuscript; P.T. J.B. C.K. and H.M. generated FC and Sysmex data for the PFC; N.G. conducted the imputation of the PFC genotyping data; J.D. established the INTERVAL and provided critical comments on the manuscript; A.M. provided clinical and biological interpretations; J.W.M.H. provided in vitro data on thrombus formation phenotypes; W.H.O. established the PFC and INTERVAL; K.D. supervised the experiments and oversaw analyses; and W.J.A. and E.T. supervised the project and wrote the manuscript jointly.
Funding Information:
This research has been conducted using the UK Biobank resource under application number 13745. The authors are grateful to the Lowy Foundation USA for supporting this work. The authors thank the members of the Cambridge BioResource Scientific Advisory Board and Management Committee for supporting our study and the NIHR Cambridge Biomedical Research Centre for funding (RG64219). DNA extraction and genotyping were cofunded by the National Institute for Health and Care Research (NIHR), the NIHR BioResource , and the NIHR Cambridge Biomedical Research Centre ( BRC-1215-20014 ). The academic coordinating centre for INTERVAL was supported by core funding from the NIHR Blood and Transplant Research Unit in Donor Health and Genomics ( NIHR BTRU-2014-10024 ), the NIHR Blood and Transplant Research Unit in Donor Health and Behaviour ( NIHR203337 ), the UK Medical Research Council ( MR/L003120/1 ), the British Heart Foundation ( SP/09/002 , RG/13/13/30194 , and RG/18/13/33946 ) and the NIHR Cambridge BRC ( BRC-1215-20014 and NIHR203312 ). W.J.A. is supported financially by NHS Blood and Transplant.
Publisher Copyright:
© 2023 The American Society of Hematology