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Blood. 2015 Sep 10;126(11):e19-29. doi: 10.1182/blood-2015-02-624551. Epub 2015 Jun 23.

Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF.

Author information

  • 1Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom; The Framingham Heart Study, Cardiovascular Epidemiology and Human Genomics Branch, National Heart, Lung, and Blood Institute, Framingham, MA; The Framingham Heart Study, Framingham, MA, and the Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD;
  • 2Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands;
  • 3Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX;
  • 4Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden;
  • 5Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany;
  • 6Joseph J. Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI;
  • 7Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA;
  • 8Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA; Harvard Medical School, Boston, MA;
  • 9Department of Neurology, Boston University School of Medicine, Boston, MA;
  • 10The Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, and Department of Pediatrics, Harbor-University of California at Los Angeles (UCLA) Medical Center, Torrance, CA;
  • 11Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX; Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX;
  • 12Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom; Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom; Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia;
  • 13Institute of Genetic Epidemiology, Helmholtz Centre Munich-German Research Center for Environmental Health, Neuherberg, Germany; Department of Medicine I, Ludwig-Maximilians-University Munich, Munich, Germany; German Centre for Cardiovascular Research, partner site Munich Heart Alliance, Munich, Germany;
  • 14GeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD;
  • 15Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN;
  • 16Department of Hematology, Erasmus MC, Rotterdam, The Netherlands;
  • 17Departments of Medicine and Pathology, University of Vermont, Colchester, VT;
  • 18University of California at Davis, Davis, CA;
  • 19Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden; Science for Life Laboratory, Karolinska Institute, Stockholm, Sweden;
  • 20Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom; Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom;
  • 21Department of Public Health, Faculty of Medicine, University of Split, Split, Croatia;
  • 22Institute of Epidemiology II, Helmholtz Centre Munich-German Research Center for Environmental Health, Neuherberg, Germany; Department of Internal Medicine II-Cardiology, University of Ulm Medical School, Ulm, Germany;
  • 23Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands;
  • 24Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA;
  • 25Radcliffe Department of Medicine, Division of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom;
  • 26Study of Health in Pomerania/ Clinical and Epidemiological Research Department, Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany;
  • 27GeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD;
  • 28The Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, and.
  • 29Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN;
  • 30The Framingham Heart Study, Framingham, MA, and the Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD;
  • 31German Centre for Cardiovascular Research, partner site Munich Heart Alliance, Munich, Germany; Institute of Epidemiology II, Helmholtz Centre Munich-German Research Center for Environmental Health, Neuherberg, Germany; Research Unit of Molecular Epidemiology, Helmholtz Centre Munich-German Research Center for Environmental Health, Neuherberg, Germany;
  • 32GeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD; Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD;
  • 33Institute of Immunology and Transfusion Medicine, Department of Transfusion Medicine, University Medicine Greifswald, Greifswald, Germany;
  • 34Fred Hutchinson Cancer Research Center, Seattle, WA;
  • 35Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom; Alzheimer Scotland Dementia Research Centre, Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom;
  • 36Institute of Genetic Epidemiology, Helmholtz Centre Munich-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-University, Munich, Germany;
  • 37Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom;
  • 38Department of Biostatistics, University of Washington, Seattle, WA;
  • 39GeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD; Division of Allergy and Clinical Immunology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD;
  • 40Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA; Department of Epidemiology, and Department of Health Services, University of Washington, Seattle, WA; Group Health Research Institute, Group Health Cooperative, Seattle, WA;
  • 41Royal North Shore Hospital, University of Sydney, Sydney, NSW, Australia;
  • 42Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom; Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom;
  • 43Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX;
  • 44Department of Internal Medicine II-Cardiology, University of Ulm Medical School, Ulm, Germany; German Heart Centre Munich, Munich Technical University, Munich, Germany; and.
  • 45Fred Hutchinson Cancer Research Center, Seattle, WA; Department of Epidemiology, and.
  • 46The Framingham Heart Study, Cardiovascular Epidemiology and Human Genomics Branch, National Heart, Lung, and Blood Institute, Framingham, MA;
  • 47Department of Epidemiology, and Group Health Research Institute, Group Health Cooperative, Seattle, WA; Seattle Epidemiologic Research and Information Center, Veterans Affairs Office of Research and Development, Seattle, WA.

Abstract

Fibrinogen, coagulation factor VII (FVII), and factor VIII (FVIII) and its carrier von Willebrand factor (vWF) play key roles in hemostasis. Previously identified common variants explain only a small fraction of the trait heritabilities, and additional variations may be explained by associations with rarer variants with larger effects. The aim of this study was to identify low-frequency (minor allele frequency [MAF] ≥0.01 and <0.05) and rare (MAF <0.01) variants that influence plasma concentrations of these 4 hemostatic factors by meta-analyzing exome chip data from up to 76,000 participants of 4 ancestries. We identified 12 novel associations of low-frequency (n = 2) and rare (n = 10) variants across the fibrinogen, FVII, FVIII, and vWF traits that were independent of previously identified associations. Novel loci were found within previously reported genes and had effect sizes much larger than and independent of previously identified common variants. In addition, associations at KCNT1, HID1, and KATNB1 identified new candidate genes related to hemostasis for follow-up replication and functional genomic analysis. Newly identified low-frequency and rare-variant associations accounted for modest amounts of trait variance and therefore are unlikely to increase predicted trait heritability but provide new information for understanding individual variation in hemostasis pathways.

PMID:
26105150
[PubMed - indexed for MEDLINE]
PMCID:
PMC4566813
Free PMC Article
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