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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

1
Medical 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;
2
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands;
3
Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX;
4
Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden;
5
Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany;
6
Joseph J. Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI;
7
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA;
8
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA; Harvard Medical School, Boston, MA;
9
Department of Neurology, Boston University School of Medicine, Boston, MA;
10
The 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;
11
Human 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;
12
Centre 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;
13
Institute 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;
14
GeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD;
15
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN;
16
Department of Hematology, Erasmus MC, Rotterdam, The Netherlands;
17
Departments of Medicine and Pathology, University of Vermont, Colchester, VT;
18
University of California at Davis, Davis, CA;
19
Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden; Science for Life Laboratory, Karolinska Institute, Stockholm, Sweden;
20
Centre 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;
21
Department of Public Health, Faculty of Medicine, University of Split, Split, Croatia;
22
Institute 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;
23
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands;
24
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA;
25
Radcliffe Department of Medicine, Division of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom;
26
Study of Health in Pomerania/ Clinical and Epidemiological Research Department, Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany;
27
GeneSTAR 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;
28
The Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, and.
29
Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN;
30
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;
31
German 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;
32
GeneSTAR 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;
33
Institute of Immunology and Transfusion Medicine, Department of Transfusion Medicine, University Medicine Greifswald, Greifswald, Germany;
34
Fred Hutchinson Cancer Research Center, Seattle, WA;
35
Centre 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;
36
Institute 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;
37
Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom;
38
Department of Biostatistics, University of Washington, Seattle, WA;
39
GeneSTAR 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;
40
Cardiovascular 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;
41
Royal North Shore Hospital, University of Sydney, Sydney, NSW, Australia;
42
Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom; Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom;
43
Human 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;
44
Department of Internal Medicine II-Cardiology, University of Ulm Medical School, Ulm, Germany; German Heart Centre Munich, Munich Technical University, Munich, Germany; and.
45
Fred Hutchinson Cancer Research Center, Seattle, WA; Department of Epidemiology, and.
46
The Framingham Heart Study, Cardiovascular Epidemiology and Human Genomics Branch, National Heart, Lung, and Blood Institute, Framingham, MA;
47
Department 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
PMCID:
PMC4566813
DOI:
10.1182/blood-2015-02-624551
[Indexed for MEDLINE]
Free PMC Article

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