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Am J Hum Genet. 2016 Jul 7;99(1):40-55. doi: 10.1016/j.ajhg.2016.05.005. Epub 2016 Jun 23.

Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals.

Eicher JD1, Chami N2, Kacprowski T3, Nomura A4, Chen MH1, Yanek LR5, Tajuddin SM6, Schick UM7, Slater AJ8, Pankratz N9, Polfus L10, Schurmann C7, Giri A11, Brody JA12, Lange LA13, Manichaikul A14, Hill WD15, Pazoki R16, Elliot P17, Evangelou E18, Tzoulaki I18, Gao H17, Vergnaud AC17, Mathias RA19, Becker DM5, Becker LC20, Burt A21, Crosslin DR22, Lyytikäinen LP23, Nikus K24, Hernesniemi J25, Kähönen M26, Raitoharju E23, Mononen N23, Raitakari OT27, Lehtimäki T23, Cushman M28, Zakai NA28, Nickerson DA29, Raffield LM13, Quarells R30, Willer CJ31, Peloso GM32, Abecasis GR33, Liu DJ34; Global Lipids Genetics Consortium, Deloukas P35, Samani NJ36, Schunkert H37, Erdmann J38; CARDIoGRAM Exome Consortium; Myocardial Infarction Genetics Consortium, Fornage M39, Richard M39, Tardif JC2, Rioux JD2, Dube MP2, de Denus S40, Lu Y41, Bottinger EP41, Loos RJ41, Smith AV42, Harris TB43, Launer LJ43, Gudnason V42, Velez Edwards DR44, Torstenson ES11, Liu Y45, Tracy RP46, Rotter JI47, Rich SS14, Highland HM48, Boerwinkle E49, Li J50, Lange E51, Wilson JG52, Mihailov E53, Mägi R53, Hirschhorn J54, Metspalu A53, Esko T55, Vacchi-Suzzi C56, Nalls MA57, Zonderman AB6, Evans MK6, Engström G58, Orho-Melander M58, Melander O58, O'Donoghue ML59, Waterworth DM60, Wallentin L61, White HD62, Floyd JS12, Bartz TM63, Rice KM63, Psaty BM64, Starr JM65, Liewald DC15, Hayward C66, Deary IJ15, Greinacher A67, Völker U3, Thiele T67, Völzke H68, van Rooij FJ16, Uitterlinden AG69, Franco OH16, Dehghan A16, Edwards TL11, Ganesh SK70, Kathiresan S71, Faraday N72, Auer PL73, Reiner AP74, Lettre G2, Johnson AD75.

Author information

1
Population Sciences Branch, National Heart Lung and Blood Institute, The Framingham Heart Study, Framingham, MA 01702, USA.
2
Department of Medicine, Université de Montréal, Montréal, QC H3T 1J4, Canada; Montreal Heart Institute, Montréal, QC H1T 1C8, Canada.
3
Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald and Ernst-Mortiz-Arndt University Greifswald, Greifswald 17475, Germany; DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.
4
Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa 9200942, Japan.
5
Department of Medicine, Division of General Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
6
Laboratory of Epidemiology and Population Sciences, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
7
The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
8
Genetics, Target Sciences, GlaxoSmithKline, Research Triangle Park, NC 27709, USA; OmicSoft Corporation, Cary, NC 27513, USA.
9
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55454, USA.
10
Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
11
Division of Epidemiology, Institute for Medicine and Public Health, Vanderbilt University, Nashville, TN 37235, USA.
12
Department of Medicine, University of Washington, Seattle, WA 98101, USA.
13
Department of Genetics, University of North Carolina, Chapel Hill, NC 27514, USA.
14
Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA.
15
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK; Department of Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK.
16
Department of Epidemiology, Erasmus MC, Rotterdam 3000, the Netherlands.
17
Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London W2 1PG, UK.
18
Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London W2 1PG, UK; Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina 45110, Greece.
19
Department of Medicine, Division of General Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Divisions of Allergy and Clinical Immunology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
20
Department of Medicine, Division of General Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Divisions of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
21
Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
22
Department of Biomedical Informatics and Medical Education, University of Washington, Seattle, WA 98105, USA.
23
Department of Clinical Chemistry, Fimlab Laboratories, Tampere 33520, Finland; Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere 33514, Finland.
24
Department of Cardiology, Heart Center, Tampere University Hospital, Tampere 33521, Finland; University of Tampere, School of Medicine, Tampere 33514, Finland.
25
Department of Clinical Chemistry, Fimlab Laboratories, Tampere 33520, Finland; Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere 33514, Finland; Department of Cardiology, Heart Center, Tampere University Hospital, Tampere 33521, Finland.
26
Department of Clinical Physiology, Tampere University Hospital, Tampere 33521, Finland; Department of Clinical Physiology, University of Tampere, Tampere 33514, Finland.
27
Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku 20521, Finland; Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku 20520, Finland.
28
Departments of Medicine and Pathology, University of Vermont College of Medicine, Burlington, VT 05405, USA.
29
Department of Genome Sciences, University of Washington, Seattle, WA 98105, USA.
30
Morehouse School of Medicine, Social Epidemiology Research Center, Cardiovascular Research Institute, Atlanta, GA 30310, USA.
31
Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48108, USA; Department of Computational Medicine and Bioinformatics, Department of Human Genetics, University of Michigan, Ann Arbor, MI 48108, USA; Department of Biostatistics, University of Michigan, Ann Arbor, MI 48108, USA.
32
Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.
33
Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, MI 48108, USA.
34
Department of Public Health Sciences, College of Medicine, Pennsylvania State University, Hershey, PA 17033, USA.
35
William Harvey Research Institute, Queen Mary University London, London E1 4NS, UK; Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah 21589, Saudi Arabia.
36
Department of Cardiovascular Sciences, University of Leicester, Leicester LE1 7RH, UK; NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester LE3 9QP, UK.
37
DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich 80333, Germany; Deutsches Herzzentrum München, Technische Universität München, Munich 80333, Germany.
38
Institute for Integrative and Experimental Genomics, University of Lübeck, Lübeck 23562, Germany; DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck 23562, Germany.
39
Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
40
Montreal Heart Institute, Montréal, QC H1T 1C8, Canada; Faculty of Pharmacy, Université de Montréal, Montréal, QC H3T 1J4, Canada.
41
The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
42
Icelandic Heart Association, Kopavogur 201, Iceland; Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland.
43
Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, Intramural Research Program, NIH, Bethesda, MD 21224, USA.
44
Vanderbilt Epidemiology Center, Department of Obstetrics & Gynecology, Institute for Medicine and Public Health, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN 37203, USA.
45
Center for Human Genetics, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
46
Departments of Pathology and Laboratory Medicine and Biochemistry, University of Vermont College of Medicine, Colchester, VT 05446, USA.
47
Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, Torrance, CA 90502, USA; Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
48
The University of Texas School of Public Health, The University of Texas Graduate School of Biomedical Sciences at Houston, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27514, USA.
49
Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
50
Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Palo Alto, CA 94305, USA.
51
Department of Genetics, University of North Carolina, Chapel Hill, NC 27514, USA; Department of Biostatistics, University of North Carolina, Chapel Hill, NC 27514, USA.
52
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA.
53
Estonian Genome Center, University of Tartu, Tartu 51010, Estonia.
54
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Department of Endocrinology, Boston Children's Hospital, Boston, MA 02115, USA.
55
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Estonian Genome Center, University of Tartu, Tartu 51010, Estonia.
56
Department of Family, Population and Preventive Medicine, Stony Brook University, Stony Brook, NY 11794, USA.
57
Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD 21224, USA.
58
Department of Clinical Sciences Malmö, Lund University, Malmö 221 00, Sweden; Skåne University Hospital, Malmö 222 41, Sweden.
59
TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA.
60
Genetics, Target Sciences, GlaxoSmithKline, King of Prussia, PA 19406, USA.
61
Department of Medical Sciences, Cardiology, and Uppsala Clinical Research Center, Uppsala University, Uppsala 751 85, Sweden.
62
Green Lane Cardiovascular Service, Auckland City Hospital and University of Auckland, Auckland 1142, New Zealand.
63
Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
64
Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle, WA 98101, USA; Group Health Research Institute, Group Health Cooperative, Seattle, WA 98101, USA.
65
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK; Alzheimer Scotland Research Centre, Edinburgh EH8 9JZ, UK.
66
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
67
Institute for Immunology and Transfusion Medicine, University Medicine Greifswald, Greifswald 17475, Germany.
68
DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany; Institute for Community Medicine, University Medicine Greifswald, Greifswald 13347, Germany.
69
Department of Epidemiology, Erasmus MC, Rotterdam 3000, the Netherlands; Department of Internal Medicine, Erasmus MC, Rotterdam 3000, the Netherlands; Netherlands Consortium for Healthy Ageing (NCHA), Rotterdam 3015, the Netherlands.
70
Departments of Internal and Human Genetics, University of Michigan, Ann Arbor, MI 48108, USA.
71
Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
72
Department of Anesthesiology & Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
73
Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI 53205, USA.
74
Department of Epidemiology, University of Washington, Seattle, WA 98105, USA; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
75
Population Sciences Branch, National Heart Lung and Blood Institute, The Framingham Heart Study, Framingham, MA 01702, USA. Electronic address: johnsonad2@nhlbi.nih.gov.

Abstract

Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets' important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common (ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV (PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.

PMID:
27346686
PMCID:
PMC5005441
DOI:
10.1016/j.ajhg.2016.05.005
[Indexed for MEDLINE]
Free PMC Article

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