Abstract
BACKGROUND: Blood platelets are mediators of atherothrombotic disease and are regulated by complex sets of genes. Association studies in European ancestry populations have already detected informative platelet regulatory loci. Studies in other ancestries can potentially reveal new associations because of different allele frequencies, linkage structures, and variant effects.
OBJECTIVES: To reveal new regulatory genes for platelet count (PLT).
METHODS: Genome-wide association studies (GWAS) were performed in 20,218 Bangladeshi and 9198 Pakistani individuals from the Genes & Health study. Loci significantly associated with PLT underwent fine-mapping to identify candidate genes.
RESULTS: Of 1588 significantly associated variants ( P < 5 × 10 -8) at 20 loci in the Bangladeshi analysis, most replicated findings in prior transancestry GWAS and in the Pakistani analysis. However, the Bangladeshi locus defined by rs946528 (chr1:46019890) did not associate with PLT in the Pakistani analysis but was in the same linkage disequilibrium block ( r 2 ≥ 0.5) as PLT-associated variants in prior East Asian GWAS. The single independent association signal was refined to a 95% credible set of 343 variants spanning 8 coding genes. Functional annotation, mapping to megakaryocyte regulatory regions, and colocalization with blood expression quantitative trait loci identified the likely mediator of the PLT phenotype to be PIK3R3 encoding a regulator of phosphoinositol 3-kinase (PI3K).
CONCLUSION: Abnormal PI3K activity in the vessel wall is already implicated in the pathogenesis of atherothrombosis. Our identification of a new association between PIK3R3 and PLT provides further mechanistic insights into the contribution of the PI3K pathway to platelet biology.
| Original language | English |
|---|---|
| Article number | 100175 |
| Journal | Research and Practice in Thrombosis and Haemostasis |
| Volume | 7 |
| Issue number | 4 |
| Early online date | 14 May 2023 |
| DOIs | |
| Publication status | Published - 19 May 2023 |
Bibliographical note
Funding Information:K.B. is funded by a GW4-CAT Wellcome Trust Fellowship (216277/Z/19/Z). For open access, the author has applied a CC BY public copyright license to any author-accepted manuscript arising from this submission. Genes & Health is/has recently been core-funded by Wellcome (WT102627 and WT210561), the Medical Research Council (UK) (M009017), Higher Education Funding Council for England Catalyst, Barts Charity (845/1796), Health Data Research UK (for London substantive site), and research delivery support from the NHS National Institute for Health Research Clinical Research Network (North Thames). Genes & Health is/has recently been funded by Alnylam Pharmaceuticals , Genomics PLC, and a Life Sciences Industry Consortium of Bristol-Myers Squibb Company , GlaxoSmithKline Research and Development Limited, Maze Therapeutics Inc, Merck Sharp & Dohme LLC, Novo Nordisk A/S, Pfizer Inc, and Takeda Development Centre Americas Inc. D.V. is a member of the Health Protection Research Unit in Chemical and Radiation Threats and Hazards, a partnership between Public Health England and Imperial College London , which is funded by the National Institute for Health Research .
Funding Information:
The Genes & Health Research Team thank Social Action for Health, Centre of The Cell, members of our Community Advisory Group, and staff who recruited and collected data from volunteers. We thank the National Institute for Health Research National Biosample Centre (UK Biocentre), the Social Genetic & Developmental Psychiatry Centre (King's College London), Wellcome Sanger Institute, and Broad Institute for sample processing, genotyping, sequencing, and variant annotation. We also thank Barts Health NHS Trust, NHS Clinical Commissioning Groups (City and Hackney, Waltham Forest, Tower Hamlets, Newham, Redbridge, Havering, and Barking and Dagenham), East London NHS Foundation Trust, Bradford Teaching Hospitals NHS Foundation Trust, Public Health England (especially David Wyllie), Discovery Data Service/Endeavour Health Charitable Trust (especially David Stables), and NHS Digital for GDPR-compliant data sharing backed by individual written informed consent. Most of all, we thank all of the volunteers participating in Genes & Health. K.B. is funded by a GW4-CAT Wellcome Trust Fellowship (216277/Z/19/Z). For open access, the author has applied a CC BY public copyright license to any author-accepted manuscript arising from this submission. Genes & Health is/has recently been core-funded by Wellcome (WT102627 and WT210561), the Medical Research Council (UK) (M009017), Higher Education Funding Council for England Catalyst, Barts Charity (845/1796), Health Data Research UK (for London substantive site), and research delivery support from the NHS National Institute for Health Research Clinical Research Network (North Thames). Genes & Health is/has recently been funded by Alnylam Pharmaceuticals, Genomics PLC, and a Life Sciences Industry Consortium of Bristol-Myers Squibb Company, GlaxoSmithKline Research and Development Limited, Maze Therapeutics Inc, Merck Sharp & Dohme LLC, Novo Nordisk A/S, Pfizer Inc, and Takeda Development Centre Americas Inc. D.V. is a member of the Health Protection Research Unit in Chemical and Radiation Threats and Hazards, a partnership between Public Health England and Imperial College London, which is funded by the National Institute for Health Research. The Genes and Health study was approved by the London South-East NRES Committee of the Health Research Authority (14/LO/1240). K.B. performed the analyses and cowrote the manuscript. L.F. and D.v.H. contributed to the analysis. D.V. codesigned the analyses. A.D.M. conceived the study and cowrote the manuscript. There are no competing interests to disclose.
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