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Hum Mol Genet. 2016 Jan 15;25(2):358-70. doi: 10.1093/hmg/ddv454. Epub 2015 Nov 10.

A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration.

de Vries PS1, Chasman DI2, Sabater-Lleal M3, Chen MH4, Huffman JE5, Steri M6, Tang W7, Teumer A8, Marioni RE9, Grossmann V10, Hottenga JJ11, Trompet S12, Müller-Nurasyid M13, Zhao JH14, Brody JA15, Kleber ME16, Guo X17, Wang JJ18, Auer PL19, Attia JR20, Yanek LR21, Ahluwalia TS22, Lahti J23, Venturini C24, Tanaka T25, Bielak LF26, Joshi PK27, Rocanin-Arjo A28, Kolcic I29, Navarro P30, Rose LM31, Oldmeadow C20, Riess H32, Mazur J33, Basu S34, Goel A35, Yang Q36, Ghanbari M37, Willemsen G11, Rumley A38, Fiorillo E6, de Craen AJ39, Grotevendt A40, Scott R14, Taylor KD41, Delgado GE16, Yao J41, Kifley A18, Kooperberg C42, Qayyum R21, Lopez LM43, Berentzen TL44, Räikkönen K45, Mangino M46, Bandinelli S47, Peyser PA26, Wild S48, Trégouët DA28, Wright AF30, Marten J30, Zemunik T49, Morrison AC50, Sennblad B51, Tofler G52, de Maat MP53, de Geus EJ54, Lowe GD38, Zoledziewska M6, Sattar N55, Binder H33, Völker U56, Waldenberger M57, Khaw KT58, Mcknight B59, Huang J60, Jenny NS61, Holliday EG62, Qi L63, Mcevoy MG64, Becker DM21, Starr JM65, Sarin AP66, Hysi PG46, Hernandez DG67, Jhun MA26, Campbell H68, Hamsten A3, Rivadeneira F69, Mcardle WL70, Slagboom PE71, Zeller T72, Koenig W73, Psaty BM74, Haritunians T75, Liu J42, Palotie A76, Uitterlinden AG69, Stott DJ77, Hofman A1, Franco OH1, Polasek O78, Rudan I68, Morange PE79, Wilson JF80, Kardia SL26, Ferrucci L25, Spector TD46, Eriksson JG81, Hansen T82, Deary IJ83, Becker LC21, Scott RJ84, Mitchell P18, März W85, Wareham NJ14, Peters A86, Greinacher A87, Wild PS88, Jukema JW89, Boomsma DI11, Hayward C30, Cucca F6, Tracy R90, Watkins H35, Reiner AP91, Folsom AR7, Ridker PM2, O'Donnell CJ92, Smith NL93, Strachan DP94, Dehghan A95.

Author information

1
Department of Epidemiology.
2
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA, Harvard Medical School, Boston, MA, USA.
3
Department of Medicine, Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit and.
4
Department of Neurology, Boston University School of Medicine, Boston, MA, USA, Framingham Heart Study, Population Sciences Branch, Division of Intramural Research National Heart Lung and Blood Institute, National Institutes of Health, Framingham, MA, USA.
5
Framingham Heart Study, Population Sciences Branch, Division of Intramural Research National Heart Lung and Blood Institute, National Institutes of Health, Framingham, MA, USA, MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine.
6
Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionaledelle Ricerche, Monserrato, Cagliari, Italy.
7
Division of Epidemiology and Community Health and.
8
Institute for Community Medicine.
9
Centre for Cognitive Ageing and Cognitive Epidemiology, Centre for Genomic and Experimental Medicine, Queensland Brain Institute, University of Queensland, Brisbane, Australia.
10
Center for Thrombosis and Hemostasis (CTH).
11
Department of Biological Psychology, Netherlands Twin Register, VU University, Amsterdam, The Netherlands.
12
Department of Cardiology, Department of Gerontology and Geriatrics and.
13
Institute of Genetic Epidemiology, Department of Medicine I, Ludwig-Maximilians-University Munich, Munich, Germany, DZHK (German Centre for Cardiovascular Research) and.
14
MRC Epidemiology Unit, School of Clinical Medicine and.
15
Department of Medicine.
16
Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
17
Institute for Translational Genomics and Population Sciences and Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor/UCLA Medical Center, Torrance, CA, USA.
18
Department of Ophthalmology, Centre for Vision Research, Westmead Millennium Institute for Medical Research, University of Sydney, Sydney, Australia.
19
Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI, USA.
20
Public Health Stream and School of Medicine and Public Health and.
21
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
22
Novo Nordisk Foundation Centre for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences and Copenhagen Prospective Studies on Asthma in Childhood, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark, The Danish Pediatric Asthma Center, Gentofte Hospital, The Capital Region, Copenhagen, Denmark.
23
Institute of Behavioural Sciences, Folkhälsan Research Centre, Helsinki, Finland.
24
Institute of Opthalmology, UCL, London, UK, Department of Twin Research and Genetic Epidemiology, Kings College London, London, UK.
25
Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, USA.
26
Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA.
27
Centre for Population Health Sciences, Usher Institute of Population Health Sciences and Informatics, Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics.
28
Institut National pour la Santé et la Recherche Médicale (INSERM), Unité Mixte de Recherche en Santé (UMR_S) 1166, Paris F-75013, France, Sorbonne Universités, Université Pierre et Marie Curie (UPMC Univ Paris 06), UMR_S 1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris F-75013, France, Institute for Cardiometabolism and Nutrition (ICAN), Paris F-75013, France.
29
Department of Public Health, Faculty of Medicine.
30
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine.
31
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA.
32
Institute of Epidemiology II and.
33
Institute of Medical Biostatistics, Epidemiology and Informatics and.
34
Division of Biostatistics, University of Minnesota, Minneapolis, MN, USA.
35
Cardiovascular Medicine Department/Radcliffe Department of Medicine, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
36
Framingham Heart Study, Population Sciences Branch, Division of Intramural Research National Heart Lung and Blood Institute, National Institutes of Health, Framingham, MA, USA, Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
37
Department of Epidemiology, Department of Genetics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
38
Institute of Cardiovascular and Medical Sciences and.
39
Department of Gerontology and Geriatrics and.
40
Institute of Clinical Chemistry and Laboratory Medicine.
41
Institute for Translational Genomics and Population Sciences and.
42
Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
43
Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychiatry, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland, University College Dublin, UCD Conway Institute, Centre for Proteome Research, UCD, Belfield, Dublin, Ireland.
44
Institute of Preventive Medicine, Bispebjerg and Frederiksberg Hospital, The Capital Region, Copenhagen, Denmark.
45
Institute of Behavioural Sciences.
46
Department of Twin Research and Genetic Epidemiology, Kings College London, London, UK.
47
Geriatric Unit, Azienda Sanitaria Firenze (ASF), Florence, Italy.
48
Centre for Population Health Sciences, Usher Institute of Population Health Sciences and Informatics.
49
Department of Biology, School of Medicine and.
50
Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX, USA.
51
Department of Medicine, Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit and Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.
52
Royal North Shore Hospital, Sydney University, Sydney, Australia.
53
Department of Hematology and.
54
Department of Biological Psychology, Netherlands Twin Register, VU University, Amsterdam, The Netherlands, EMGO+ institute, VU University & VU Medical Center, Amsterdam.
55
Faculty of Medicine, BHF Glasgow Cardiovascular Research Centre, Glasgow, UK.
56
Interfaculty Institute for Genetics and Functional Genomics and.
57
Institute of Epidemiology II and Research Unit of Molecular Epidemiology, Helmholtz ZentrumMünchen - German Research Center for Environmental Health, Neuherberg, Germany.
58
Clinical Gerontology Unit, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
59
Department of Biostatistics.
60
Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
61
Department of Pathology and Laboratory Medicine and.
62
Public Health Stream, Hunter Medical Research Institute, School of Medicine and Public Health and.
63
Division of Biostatistics, Department of Public Health Sciences, UC Davis, Davis, CA, USA.
64
School of Medicine and Public Health, University of Newcastle, Newcastle, Australia.
65
Centre for Cognitive Ageing and Cognitive Epidemiology, Alzheimer Scotland Dementia Research Centre and.
66
Institute for Molecular Medicine Finland (FIMM) and Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland.
67
Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
68
Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics.
69
Department of Epidemiology, Department of Internal Medicine, Erasmus MC, Wytemaweg 80, Rotterdam, The Netherlands.
70
School of Social and Community Medicine, University of Bristol, Bristol, UK.
71
Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
72
Department of General and Interventional Cardiology, University Heart Centre, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, German Center for Cardiovascular Research (DZHK), Partner Site Hamburg, Lübeck, Kiel, Hamburg, Germany.
73
German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany, Department of Internal Medicine II - Cardiology, University of Ulm Medical Centre, Ulm, Germany, Deutsches Herzzentrum München, Technische Universität München, Munich, Germany.
74
Department of Medicine, Epidemiology, and Health Services and Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA.
75
Inflammatory Bowel & Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
76
Institute for Molecular Medicine Finland (FIMM) and.
77
Institute of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow, Glasgow, UK.
78
Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, Department of Public Health, Faculty of Medicine, Centre for Global Health, University of Split, Split, Croatia.
79
Laboratory of Haematology, La Timone Hospital, Marseille F-13385, France, INSERM, UMR_S 1062, Nutrition Obesity and Risk of Thrombosis, Marseille F-13385, France, Aix-Marseille University, UMR_S 1062, Nutrition Obesity and Risk of Thrombosis, Marseille F-13385, France.
80
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics.
81
Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland, Folkhälsan Research Centre, Helsinki, Finland, National Institute for Health and Welfare, Helsinki, Finland, Unit of General Practice, Helsinki University Central Hospital, Helsinki, Finland.
82
Novo Nordisk Foundation Centre for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences and.
83
Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh, UK.
84
Information based Medicine Program, Hunter Medical Research Institute, New Lambton Heights, Australia, School of Biomedical Sciences and Pharmacy, University of Newcastle, New Lambton Heights, Australia.
85
Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany, Synlab Academy, Synlab Services LLC, Mannheim, Germany, Clinical Institute of Medical, Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
86
Institute of Epidemiology II and DZHK (German Centre for Cardiovascular Research) and.
87
Institute for Immunology and Transfusion Medicine, University Medicine Greifswald, Greifswald, Germany.
88
Center for Thrombosis and Hemostasis (CTH), Preventive Cardiology and Preventive Medicine, Department of Medicine 2, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany, German Center for Cardiovascular Research (DZHK), Partner Site RheinMain, Mainz, Germany.
89
Department of Cardiology, Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands, Interuniversity Cardiology Institute of The Netherlands, Utrecht, The Netherlands.
90
Department of Pathology and Laboratory Medicine, Center for Clinical and Translational Sciences, University of Vermont College of Medicine, Colchester, VT, USA.
91
Fred Hutchinson Cancer Research Center, Seattle, WA, USA, University of Washington, Seattle, WA, USA.
92
Framingham Heart Study, Population Sciences Branch, Division of Intramural Research National Heart Lung and Blood Institute, National Institutes of Health, Framingham, MA, USA, National Heart, Lung and Blood Institute, Division of Intramural Research, Cardiology Division, Massachusetts General Hospital, Boston, MA, USA.
93
Department of Epidemiology, University of Washington, Seattle, WA, USA, Institute of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow, Glasgow, UK, Department of Veterans Affairs, Office of Research and Development, Seattle Epidemiologic Research and Information Center, Seattle, WA, USA and.
94
Population Health Research Institute, St George's University of London, London, UK.
95
Department of Epidemiology, a.dehghan@erasmusmc.nl.

Abstract

Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ∼120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.

PMID:
26561523
PMCID:
PMC4715256
DOI:
10.1093/hmg/ddv454
[Indexed for MEDLINE]
Free PMC Article

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