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Eicher JD, Chami N, Kacprowski T, Nomura A, Chen MH, Yanek LR, Tajuddin SM, Schick UM, Slater AJ, Pankratz N, Polfus L, Schurmann C, Giri A, Brody JA, Lange LA, Manichaikul A, Hill WD, Pazoki R, Elliot P, Evangelou E, Tzoulaki I, Gao H, Vergnaud AC, Mathias RA, Becker DM, Becker LC, Burt A, Crosslin DR, Lyytikäinen LP, Nikus K, Hernesniemi J, Kähönen M, Raitoharju E, Mononen N, Raitakari OT, Lehtimäki T, Cushman M, Zakai NA, Nickerson DA, Raffield LM, Quarells R, Willer CJ, Peloso GM, Abecasis GR, Liu DJ, Deloukas P, Samani NJ, Schunkert H, Erdmann J, Fornage M, Richard M, Tardif JC, Rioux JD, Dube MP, de Denus S, Lu Y, Bottinger EP, Loos RJF, Smith AV, Harris TB, Launer LJ, Gudnason V, Velez Edwards DR, Torstenson ES, Liu Y, Tracy RP, Rotter JI, Rich SS, Highland HM, Boerwinkle E, Li J, Lange E, Wilson JG, Mihailov E, Mägi R, Hirschhorn J, Metspalu A, Esko T, Vacchi-Suzzi C, Nalls MA, Zonderman AB, Evans MK, Engström G, Orho-Melander M, Melander O, O'Donoghue ML, Waterworth DM, Wallentin L, White HD, Floyd JS, Bartz TM, Rice KM, Psaty BM, Starr JM, Liewald DCM, Hayward C, Deary IJ, Greinacher A, Völker U, Thiele T, Völzke H, van Rooij FJA, Uitterlinden AG, Franco OH, Dehghan A, Edwards TL, Ganesh SK, Kathiresan S, Faraday N, Auer PL, Reiner AP, Lettre G, Johnson AD. Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals. Am J Hum Genet 2016; 99:40-55. [PMID: 27346686 PMCID: PMC5005441 DOI: 10.1016/j.ajhg.2016.05.005] [Citation(s) in RCA: 67] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Accepted: 05/03/2016] [Indexed: 12/13/2022] Open
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.
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Affiliation(s)
- John D Eicher
- Population Sciences Branch, National Heart Lung and Blood Institute, The Framingham Heart Study, Framingham, MA 01702, USA
| | - Nathalie Chami
- Department of Medicine, Université de Montréal, Montréal, QC H3T 1J4, Canada; Montreal Heart Institute, Montréal, QC H1T 1C8, Canada
| | - Tim Kacprowski
- 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
| | - Akihiro Nomura
- 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
| | - Ming-Huei Chen
- Population Sciences Branch, National Heart Lung and Blood Institute, The Framingham Heart Study, Framingham, MA 01702, USA
| | - Lisa R Yanek
- Department of Medicine, Division of General Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Salman M Tajuddin
- Laboratory of Epidemiology and Population Sciences, National Institute on Aging, NIH, Baltimore, MD 21224, USA
| | - Ursula M Schick
- 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
| | - Andrew J Slater
- Genetics, Target Sciences, GlaxoSmithKline, Research Triangle Park, NC 27709, USA; OmicSoft Corporation, Cary, NC 27513, USA
| | - Nathan Pankratz
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55454, USA
| | - Linda Polfus
- Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Claudia Schurmann
- 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
| | - Ayush Giri
- Division of Epidemiology, Institute for Medicine and Public Health, Vanderbilt University, Nashville, TN 37235, USA
| | - Jennifer A Brody
- Department of Medicine, University of Washington, Seattle, WA 98101, USA
| | - Leslie A Lange
- Department of Genetics, University of North Carolina, Chapel Hill, NC 27514, USA
| | - Ani Manichaikul
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA
| | - W David Hill
- Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK; Department of Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK
| | - Raha Pazoki
- Department of Epidemiology, Erasmus MC, Rotterdam 3000, the Netherlands
| | - Paul Elliot
- Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London W2 1PG, UK
| | - Evangelos Evangelou
- 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
| | - Ioanna Tzoulaki
- 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
| | - He Gao
- Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London W2 1PG, UK
| | - Anne-Claire Vergnaud
- Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London W2 1PG, UK
| | - Rasika A Mathias
- 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
| | - Diane M Becker
- Department of Medicine, Division of General Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Lewis C Becker
- 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
| | - Amber Burt
- Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA
| | - David R Crosslin
- Department of Biomedical Informatics and Medical Education, University of Washington, Seattle, WA 98105, USA
| | - Leo-Pekka Lyytikäinen
- Department of Clinical Chemistry, Fimlab Laboratories, Tampere 33520, Finland; Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere 33514, Finland
| | - Kjell Nikus
- Department of Cardiology, Heart Center, Tampere University Hospital, Tampere 33521, Finland; University of Tampere, School of Medicine, Tampere 33514, Finland
| | - Jussi Hernesniemi
- 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
| | - Mika Kähönen
- Department of Clinical Physiology, Tampere University Hospital, Tampere 33521, Finland; Department of Clinical Physiology, University of Tampere, Tampere 33514, Finland
| | - Emma Raitoharju
- Department of Clinical Chemistry, Fimlab Laboratories, Tampere 33520, Finland; Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere 33514, Finland
| | - Nina Mononen
- Department of Clinical Chemistry, Fimlab Laboratories, Tampere 33520, Finland; Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere 33514, Finland
| | - Olli T Raitakari
- 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
| | - Terho Lehtimäki
- Department of Clinical Chemistry, Fimlab Laboratories, Tampere 33520, Finland; Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere 33514, Finland
| | - Mary Cushman
- Departments of Medicine and Pathology, University of Vermont College of Medicine, Burlington, VT 05405, USA
| | - Neil A Zakai
- Departments of Medicine and Pathology, University of Vermont College of Medicine, Burlington, VT 05405, USA
| | - Deborah A Nickerson
- Department of Genome Sciences, University of Washington, Seattle, WA 98105, USA
| | - Laura M Raffield
- Department of Genetics, University of North Carolina, Chapel Hill, NC 27514, USA
| | - Rakale Quarells
- Morehouse School of Medicine, Social Epidemiology Research Center, Cardiovascular Research Institute, Atlanta, GA 30310, USA
| | - Cristen J Willer
- 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
| | - Gina M Peloso
- 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
| | - Goncalo R Abecasis
- Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, MI 48108, USA
| | - Dajiang J Liu
- Department of Public Health Sciences, College of Medicine, Pennsylvania State University, Hershey, PA 17033, USA
| | - Panos Deloukas
- 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
| | - Nilesh J Samani
- Department of Cardiovascular Sciences, University of Leicester, Leicester LE1 7RH, UK; NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester LE3 9QP, UK
| | - Heribert Schunkert
- DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich 80333, Germany; Deutsches Herzzentrum München, Technische Universität München, Munich 80333, Germany
| | - Jeanette Erdmann
- 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
| | - Myriam Fornage
- Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Melissa Richard
- Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Jean-Claude Tardif
- Department of Medicine, Université de Montréal, Montréal, QC H3T 1J4, Canada; Montreal Heart Institute, Montréal, QC H1T 1C8, Canada
| | - John D Rioux
- Department of Medicine, Université de Montréal, Montréal, QC H3T 1J4, Canada; Montreal Heart Institute, Montréal, QC H1T 1C8, Canada
| | - Marie-Pierre Dube
- Department of Medicine, Université de Montréal, Montréal, QC H3T 1J4, Canada; Montreal Heart Institute, Montréal, QC H1T 1C8, Canada
| | - Simon de Denus
- Montreal Heart Institute, Montréal, QC H1T 1C8, Canada; Faculty of Pharmacy, Université de Montréal, Montréal, QC H3T 1J4, Canada
| | - Yingchang Lu
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Erwin P Bottinger
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Ruth J F Loos
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Albert Vernon Smith
- Icelandic Heart Association, Kopavogur 201, Iceland; Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland
| | - Tamara B Harris
- Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, Intramural Research Program, NIH, Bethesda, MD 21224, USA
| | - Lenore J Launer
- Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, Intramural Research Program, NIH, Bethesda, MD 21224, USA
| | - Vilmundur Gudnason
- Icelandic Heart Association, Kopavogur 201, Iceland; Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland
| | - Digna R Velez Edwards
- Vanderbilt Epidemiology Center, Department of Obstetrics & Gynecology, Institute for Medicine and Public Health, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN 37203, USA
| | - Eric S Torstenson
- Division of Epidemiology, Institute for Medicine and Public Health, Vanderbilt University, Nashville, TN 37235, USA
| | - Yongmei Liu
- Center for Human Genetics, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
| | - Russell P Tracy
- Departments of Pathology and Laboratory Medicine and Biochemistry, University of Vermont College of Medicine, Colchester, VT 05446, USA
| | - Jerome I Rotter
- 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
| | - Stephen S Rich
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA
| | - Heather M Highland
- 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
| | - Eric Boerwinkle
- 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
| | - Jin Li
- Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Palo Alto, CA 94305, USA
| | - Ethan Lange
- Department of Genetics, University of North Carolina, Chapel Hill, NC 27514, USA; Department of Biostatistics, University of North Carolina, Chapel Hill, NC 27514, USA
| | - James G Wilson
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA
| | - Evelin Mihailov
- Estonian Genome Center, University of Tartu, Tartu 51010, Estonia
| | - Reedik Mägi
- Estonian Genome Center, University of Tartu, Tartu 51010, Estonia
| | - Joel Hirschhorn
- Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Department of Endocrinology, Boston Children's Hospital, Boston, MA 02115, USA
| | - Andres Metspalu
- Estonian Genome Center, University of Tartu, Tartu 51010, Estonia
| | - Tõnu Esko
- Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Estonian Genome Center, University of Tartu, Tartu 51010, Estonia
| | - Caterina Vacchi-Suzzi
- Department of Family, Population and Preventive Medicine, Stony Brook University, Stony Brook, NY 11794, USA
| | - Mike A Nalls
- Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD 21224, USA
| | - Alan B Zonderman
- Laboratory of Epidemiology and Population Sciences, National Institute on Aging, NIH, Baltimore, MD 21224, USA
| | - Michele K Evans
- Laboratory of Epidemiology and Population Sciences, National Institute on Aging, NIH, Baltimore, MD 21224, USA
| | - Gunnar Engström
- Department of Clinical Sciences Malmö, Lund University, Malmö 221 00, Sweden; Skåne University Hospital, Malmö 222 41, Sweden
| | - Marju Orho-Melander
- Department of Clinical Sciences Malmö, Lund University, Malmö 221 00, Sweden; Skåne University Hospital, Malmö 222 41, Sweden
| | - Olle Melander
- Department of Clinical Sciences Malmö, Lund University, Malmö 221 00, Sweden; Skåne University Hospital, Malmö 222 41, Sweden
| | - Michelle L O'Donoghue
- TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Dawn M Waterworth
- Genetics, Target Sciences, GlaxoSmithKline, King of Prussia, PA 19406, USA
| | - Lars Wallentin
- Department of Medical Sciences, Cardiology, and Uppsala Clinical Research Center, Uppsala University, Uppsala 751 85, Sweden
| | - Harvey D White
- Green Lane Cardiovascular Service, Auckland City Hospital and University of Auckland, Auckland 1142, New Zealand
| | - James S Floyd
- Department of Medicine, University of Washington, Seattle, WA 98101, USA
| | - Traci M Bartz
- Department of Biostatistics, University of Washington, Seattle, WA 98195, USA
| | - Kenneth M Rice
- Department of Biostatistics, University of Washington, Seattle, WA 98195, USA
| | - Bruce M Psaty
- 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
| | - J M Starr
- Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK; Alzheimer Scotland Research Centre, Edinburgh EH8 9JZ, UK
| | - David C M Liewald
- Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK; Department of Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK
| | - Caroline Hayward
- MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK
| | - Ian J Deary
- Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK; Department of Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK
| | - Andreas Greinacher
- Institute for Immunology and Transfusion Medicine, University Medicine Greifswald, Greifswald 17475, Germany
| | - Uwe Völker
- 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
| | - Thomas Thiele
- Institute for Immunology and Transfusion Medicine, University Medicine Greifswald, Greifswald 17475, Germany
| | - Henry Völzke
- DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany; Institute for Community Medicine, University Medicine Greifswald, Greifswald 13347, Germany
| | | | - André G Uitterlinden
- 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
| | - Oscar H Franco
- Department of Epidemiology, Erasmus MC, Rotterdam 3000, the Netherlands
| | - Abbas Dehghan
- Department of Epidemiology, Erasmus MC, Rotterdam 3000, the Netherlands
| | - Todd L Edwards
- Division of Epidemiology, Institute for Medicine and Public Health, Vanderbilt University, Nashville, TN 37235, USA
| | - Santhi K Ganesh
- Departments of Internal and Human Genetics, University of Michigan, Ann Arbor, MI 48108, USA
| | - Sekar Kathiresan
- 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
| | - Nauder Faraday
- Department of Anesthesiology & Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Paul L Auer
- Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI 53205, USA
| | - Alex P Reiner
- Department of Epidemiology, University of Washington, Seattle, WA 98105, USA; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
| | - Guillaume Lettre
- Department of Medicine, Université de Montréal, Montréal, QC H3T 1J4, Canada; Montreal Heart Institute, Montréal, QC H1T 1C8, Canada
| | - Andrew D Johnson
- Population Sciences Branch, National Heart Lung and Blood Institute, The Framingham Heart Study, Framingham, MA 01702, USA.
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