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A genome- and phenome-wide association study to identify genetic variants influencing platelet count and volume and their pleiotropic effects

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Abstract

Platelets are enucleated cell fragments derived from megakaryocytes that play key roles in hemostasis and in the pathogenesis of atherothrombosis and cancer. Platelet traits are highly heritable and identification of genetic variants associated with platelet traits and assessing their pleiotropic effects may help to understand the role of underlying biological pathways. We conducted an electronic medical record (EMR)-based study to identify common variants that influence inter-individual variation in the number of circulating platelets (PLT) and mean platelet volume (MPV), by performing a genome-wide association study (GWAS). We characterized genetic variants associated with MPV and PLT using functional, pathway and disease enrichment analyses; we assessed pleiotropic effects of such variants by performing a phenome-wide association study (PheWAS) with a wide range of EMR-derived phenotypes. A total of 13,582 participants in the electronic MEdical Records and GEnomic network had data for PLT and 6,291 participants had data for MPV. We identified five chromosomal regions associated with PLT and eight associated with MPV at genome-wide significance (P < 5E−8). In addition, we replicated 20 SNPs [out of 56 SNPs (α: 0.05/56 = 9E−4)] influencing PLT and 22 SNPs [out of 29 SNPs (α: 0.05/29 = 2E−3)] influencing MPV in a published meta-analysis of GWAS of PLT and MPV. While our GWAS did not find any new associations, our functional analyses revealed that genes in these regions influence thrombopoiesis and encode kinases, membrane proteins, proteins involved in cellular trafficking, transcription factors, proteasome complex subunits, proteins of signal transduction pathways, proteins involved in megakaryocyte development, and platelet production and hemostasis. PheWAS using a single-SNP Bonferroni correction for 1,368 diagnoses (0.05/1368 = 3.6E−5) revealed that several variants in these genes have pleiotropic associations with myocardial infarction, autoimmune, and hematologic disorders. We conclude that multiple genetic loci influence interindividual variation in platelet traits and also have significant pleiotropic effects; the related genes are in multiple functional pathways including those relevant to thrombopoiesis.

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Acknowledgments

The eMERGE network was initiated and funded by the National Human Genome Research Institute (NHGR1), with additional funding from National Institute of General Medical Sciences (NIGMS) through the following grants: U01-HG-04599 (Mayo Clinic); U01-HG-004610 and UO1-AG-06781 (Group Health Cooperative); U01-HG-004608 (Marshfield Clinic); U01HG004609 (Northwestern University); and U01-HG-04603 (Vanderbilt University, also serving as the Administrative Coordinating Center). We also acknowledge the genotyping centers U01-HG-004424 (Broad Institute) and U01-HG-004438 (Johns Hopkins University, Center for Inherited Disease Research). Additional genotyping support was provided by a Washington State Life Sciences Discovery Fund award to the Northwest Institute of Genetic Medicine (G.P.J). Additional support for PheWAS was provided through R01-LM-010685.

Conflict of interest

The authors declare no competing financial interests.

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Authors and Affiliations

  1. Division of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA

    Khader Shameer, Keyue Ding, Hayan Jouni & Iftikhar J. Kullo

  2. Departments of Medicine and Biomedical Informatics, Vanderbilt University, Nashville, TN, 37232, USA

    Joshua C. Denny & Lisa Bastarache

  3. Department of Biostatistics, University of Washington, Seattle, WA, 98195, USA

    David R. Crosslin

  4. Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, 55905, USA

    Mariza de Andrade & Christopher G. Chute

  5. Biomedical Informatics Research Center, Marshfield Clinic, Marshfield, WI, 54449, USA

    Peggy Peissig

  6. Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA

    Jennifer A. Pacheco & Rex L. Chisholm

  7. Office of Population Genomics, National Human Genome Research Institute, 5635 Fishers Lane, Suite 3058, MSC 9307, Bethesda, MD, 20892, USA

    Rongling Li

  8. Department of Medicine, Northwestern University, Chicago, IL, 60611, USA

    Abel N. Kho

  9. Center for Systems Genomics, The Huck Institutes of the Life Sciences, Eberly College of Science, Pennsylvania State University, 512 Wartik Laboratory, University Park, PA, 16802, USA

    Marylyn D. Ritchie

  10. Department of Biomedical Informatics, Vanderbilt University School of Medicine, Room 416 Eskind Medical Library, Nashville, TN, 37232, USA

    Daniel R. Masys

  11. Group Health Research Institute, 1730 Minor Avenue, Suite 1600, Seattle, WA, 98101, USA

    Eric B. Larson

  12. Essentia Institute of Rural Health, Duluth, MN, 55805, USA

    Catherine A. McCarty

  13. Department of Pharmacology, Vanderbilt University School of Medicine, 1285 Medical Research Building IV, Nashville, TN, 37232, USA

    Dan M. Roden

  14. Department of Genome Sciences, University of Washington, 3720 15th Ave NE, Seattle, WA, 98195, USA

    Gail P. Jarvik

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  1. Khader Shameer
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  2. Joshua C. Denny
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  3. Keyue Ding
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  4. Hayan Jouni
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  5. David R. Crosslin
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  6. Mariza de Andrade
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  7. Christopher G. Chute
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  8. Peggy Peissig
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  9. Jennifer A. Pacheco
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  10. Rongling Li
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  11. Lisa Bastarache
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  12. Abel N. Kho
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  13. Marylyn D. Ritchie
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  14. Daniel R. Masys
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  15. Rex L. Chisholm
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  16. Eric B. Larson
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  17. Catherine A. McCarty
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  18. Dan M. Roden
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  19. Gail P. Jarvik
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  20. Iftikhar J. Kullo
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Correspondence to Iftikhar J. Kullo.

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Shameer, K., Denny, J.C., Ding, K. et al. A genome- and phenome-wide association study to identify genetic variants influencing platelet count and volume and their pleiotropic effects. Hum Genet 133, 95–109 (2014). https://doi.org/10.1007/s00439-013-1355-7

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  • DOI: https://doi.org/10.1007/s00439-013-1355-7

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