title: Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF.
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.
authors.affiliation: 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;
authors.forename: Jennifer E
authors.identifier: http://orcid.org/0000-0002-9672-2491
authors.initials: JE
authors.lastname: Huffman
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands;
authors.forename: Paul S
authors.initials: PS
authors.lastname: de Vries
authors.affiliation: Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX;
authors.forename: Alanna C
authors.initials: AC
authors.lastname: Morrison
authors.affiliation: Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden;
authors.forename: Maria
authors.identifier: http://orcid.org/0000-0002-0128-379X
authors.initials: M
authors.lastname: Sabater-Lleal
authors.affiliation: Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany;
authors.forename: Tim
authors.identifier: http://orcid.org/0000-0002-5393-2413
authors.initials: T
authors.lastname: Kacprowski
authors.affiliation: Joseph J. Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI;
authors.forename: Paul L
authors.initials: PL
authors.lastname: Auer
authors.affiliation: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA;
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Brody
authors.affiliation: Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA; Harvard Medical School, Boston, MA;
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Chasman
authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston, MA;
authors.forename: Ming-Huei
authors.identifier: http://orcid.org/0000-0002-7036-3160
authors.initials: MH
authors.lastname: Chen
authors.affiliation: 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;
authors.forename: Xiuqing
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authors.affiliation: 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;
authors.forename: Li-An
authors.initials: LA
authors.lastname: Lin
authors.affiliation: 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;
authors.forename: Riccardo E
authors.initials: RE
authors.lastname: Marioni
authors.affiliation: 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;
authors.forename: Martina
authors.initials: M
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authors.affiliation: GeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD;
authors.forename: Lisa R
authors.initials: LR
authors.lastname: Yanek
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN;
authors.forename: Nathan
authors.initials: N
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authors.affiliation: Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX;
authors.forename: Megan L
authors.initials: ML
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authors.affiliation: Department of Hematology, Erasmus MC, Rotterdam, The Netherlands;
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authors.identifier: http://orcid.org/0000-0001-7749-334X
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authors.affiliation: Departments of Medicine and Pathology, University of Vermont, Colchester, VT;
authors.forename: Mary
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authors.lastname: Cushman
authors.affiliation: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA;
authors.forename: Kerri L
authors.initials: KL
authors.lastname: Wiggins
authors.affiliation: University of California at Davis, Davis, CA;
authors.forename: Lihong
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authors.affiliation: Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden; Science for Life Laboratory, Karolinska Institute, Stockholm, Sweden;
authors.forename: Bengt
authors.initials: B
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authors.affiliation: 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;
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Harris
authors.affiliation: Department of Public Health, Faculty of Medicine, University of Split, Split, Croatia;
authors.forename: Ozren
authors.initials: O
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authors.affiliation: 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;
authors.forename: Helene
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authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands;
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authors.affiliation: Radcliffe Department of Medicine, Division of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom;
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authors.forename: Kent D
authors.initials: KD
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authors.affiliation: Study of Health in Pomerania/ Clinical and Epidemiological Research Department, Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany;
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authors.initials: A
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authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands;
authors.forename: André G
authors.initials: AG
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authors.affiliation: 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;
authors.forename: Dhananjay
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authors.forename: Jie
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authors.lastname: Levy
authors.affiliation: 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;
authors.forename: Melanie
authors.identifier: http://orcid.org/0000-0003-0583-5093
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authors.initials: DM
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authors.initials: AR
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authors.initials: F
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authors.affiliation: Institute of Immunology and Transfusion Medicine, Department of Transfusion Medicine, University Medicine Greifswald, Greifswald, Germany;
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authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands;
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authors.affiliation: Joseph J. Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI;
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authors.initials: CC
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authors.affiliation: Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden;
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authors.forename: Konstantin
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authors.initials: AF
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authors.forename: Rasika A
authors.initials: RA
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authors.initials: GH
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authors.affiliation: Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany;
authors.forename: Uwe
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authors.forename: Myriam
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authors.initials: W
authors.lastname: Koenig
authors.affiliation: 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;
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authors.initials: JI
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authors.affiliation: Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom;
authors.forename: Caroline
authors.identifier: http://orcid.org/0000-0002-9405-9550
authors.initials: C
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authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands;
authors.forename: Abbas
authors.initials: A
authors.lastname: Dehghan
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authors.forename: Alex P
authors.initials: AP
authors.lastname: Reiner
authors.affiliation: The Framingham Heart Study, Cardiovascular Epidemiology and Human Genomics Branch, National Heart, Lung, and Blood Institute, Framingham, MA;
authors.forename: Christopher J
authors.initials: CJ
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mesh_terms: D015331:Cohort Studies; D005167:Factor VII / Q000235:genetics* / Q000378:metabolism*; D005169:Factor VIII / Q000235:genetics* / Q000378:metabolism*; D005340:Fibrinogen / Q000235:genetics* / Q000378:metabolism*; D005787:Gene Frequency; D056726:Genetic Association Studies; D014644:Genetic Variation; D006801:Humans; D009419:Nerve Tissue Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D015221:Potassium Channels / Q000235:genetics; D000081033:Potassium Channels, Sodium-Activated; D014841:von Willebrand Factor / Q000235:genetics* / Q000378:metabolism*
chemical_list: C585122:KCNT1 protein, human; D009419:Nerve Tissue Proteins; D015221:Potassium Channels; D000081033:Potassium Channels, Sodium-Activated; D014841:von Willebrand Factor; D005167:Factor VII; D005169:Factor VIII; D005340:Fibrinogen