title: Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease.
abstract: BACKGROUND
  Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34% to 50%. Genetic variants so far identified by genome-wide association studies explain only a small proportion (<2%) of its variation.
  
  
  RESULTS
  We conducted a meta-analysis of 28 genome-wide association studies including >90 000 subjects of European ancestry, the first genome-wide association meta-analysis of fibrinogen levels in 7 studies in blacks totaling 8289 samples, and a genome-wide association study in Hispanics totaling 1366 samples. Evaluation for association of single-nucleotide polymorphisms with clinical outcomes included a total of 40 695 cases and 85 582 controls for coronary artery disease, 4752 cases and 24 030 controls for stroke, and 3208 cases and 46 167 controls for venous thromboembolism. Overall, we identified 24 genome-wide significant (P<5×10(-8)) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the 3 structural fibrinogen genes and pathways related to inflammation, adipocytokines, and thyrotrophin-releasing hormone signaling. Whereas lead single-nucleotide polymorphisms in a few loci were significantly associated with coronary artery disease, the combined effect of all 24 fibrinogen-associated lead single-nucleotide polymorphisms was not significant for coronary artery disease, stroke, or venous thromboembolism.
  
  
  CONCLUSIONS
  We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and coronary artery disease, stroke, or venous thromboembolism.
authors: Maria
authors: M
authors: Sabater-Lleal
authors: Jie
authors: J
authors: Huang
authors: Daniel
authors: D
authors: Chasman
authors: Silvia
authors: S
authors: Naitza
authors: Abbas
authors: A
authors: Dehghan
authors: Andrew D
authors: AD
authors: Johnson
authors: Alexander
authors: A
authors: Teumer
authors: Alex P
authors: AP
authors: Reiner
authors: Lasse
authors: L
authors: Folkersen
authors: Saonli
authors: S
authors: Basu
authors: Alicja R
authors: AR
authors: Rudnicka
authors: Stella
authors: S
authors: Trompet
authors: Anders
authors: A
authors: Mälarstig
authors: Jens
authors: J
authors: Baumert
authors: Joshua C
authors: JC
authors: Bis
authors: Xiuqing
authors: X
authors: Guo
authors: Jouke J
authors: JJ
authors: Hottenga
authors: So-Youn
authors: SY
authors: Shin
authors: Lorna M
authors: LM
authors: Lopez
authors: Jari
authors: J
authors: Lahti
authors: Toshiko
authors: T
authors: Tanaka
authors: Lisa R
authors: LR
authors: Yanek
authors: Tiphaine
authors: T
authors: Oudot-Mellakh
authors: James F
authors: JF
authors: Wilson
authors: Pau
authors: P
authors: Navarro
authors: Jennifer E
authors: JE
authors: Huffman
authors: Tatijana
authors: T
authors: Zemunik
authors: Susan
authors: S
authors: Redline
authors: Reena
authors: R
authors: Mehra
authors: Drazen
authors: D
authors: Pulanic
authors: Igor
authors: I
authors: Rudan
authors: Alan F
authors: AF
authors: Wright
authors: Ivana
authors: I
authors: Kolcic
authors: Ozren
authors: O
authors: Polasek
authors: Sarah H
authors: SH
authors: Wild
authors: Harry
authors: H
authors: Campbell
authors: J David
authors: JD
authors: Curb
authors: Robert
authors: R
authors: Wallace
authors: Simin
authors: S
authors: Liu
authors: Charles B
authors: CB
authors: Eaton
authors: Diane M
authors: DM
authors: Becker
authors: Lewis C
authors: LC
authors: Becker
authors: Stefania
authors: S
authors: Bandinelli
authors: Katri
authors: K
authors: Räikkönen
authors: Elisabeth
authors: E
authors: Widen
authors: Aarno
authors: A
authors: Palotie
authors: Myriam
authors: M
authors: Fornage
authors: David
authors: D
authors: Green
authors: Myron
authors: M
authors: Gross
authors: Gail
authors: G
authors: Davies
authors: Sarah E
authors: SE
authors: Harris
authors: David C
authors: DC
authors: Liewald
authors: John M
authors: JM
authors: Starr
authors: Frances M K
authors: FM
authors: Williams
authors: Peter J
authors: PJ
authors: Grant
authors: Timothy D
authors: TD
authors: Spector
authors: Rona J
authors: RJ
authors: Strawbridge
authors: Angela
authors: A
authors: Silveira
authors: Bengt
authors: B
authors: Sennblad
authors: Fernando
authors: F
authors: Rivadeneira
authors: Andre G
authors: AG
authors: Uitterlinden
authors: Oscar H
authors: OH
authors: Franco
authors: Albert
authors: A
authors: Hofman
authors: Jenny
authors: J
authors: van Dongen
authors: Gonneke
authors: G
authors: Willemsen
authors: Dorret I
authors: DI
authors: Boomsma
authors: Jie
authors: J
authors: Yao
authors: Nancy
authors: N
authors: Swords Jenny
authors: Talin
authors: T
authors: Haritunians
authors: Barbara
authors: B
authors: McKnight
authors: Thomas
authors: T
authors: Lumley
authors: Kent D
authors: KD
authors: Taylor
authors: Jerome I
authors: JI
authors: Rotter
authors: Bruce M
authors: BM
authors: Psaty
authors: Annette
authors: A
authors: Peters
authors: Christian
authors: C
authors: Gieger
authors: Thomas
authors: T
authors: Illig
authors: Anne
authors: A
authors: Grotevendt
authors: Georg
authors: G
authors: Homuth
authors: Henry
authors: H
authors: Völzke
authors: Thomas
authors: T
authors: Kocher
authors: Anuj
authors: A
authors: Goel
authors: Maria Grazia
authors: MG
authors: Franzosi
authors: Udo
authors: U
authors: Seedorf
authors: Robert
authors: R
authors: Clarke
authors: Maristella
authors: M
authors: Steri
authors: Kirill V
authors: KV
authors: Tarasov
authors: Serena
authors: S
authors: Sanna
authors: David
authors: D
authors: Schlessinger
authors: David J
authors: DJ
authors: Stott
authors: Naveed
authors: N
authors: Sattar
authors: Brendan M
authors: BM
authors: Buckley
authors: Ann
authors: A
authors: Rumley
authors: Gordon D
authors: GD
authors: Lowe
authors: Wendy L
authors: WL
authors: McArdle
authors: Ming-Huei
authors: MH
authors: Chen
authors: Geoffrey H
authors: GH
authors: Tofler
authors: Jaejoon
authors: J
authors: Song
authors: Eric
authors: E
authors: Boerwinkle
authors: Aaron R
authors: AR
authors: Folsom
authors: Lynda M
authors: LM
authors: Rose
authors: Anders
authors: A
authors: Franco-Cereceda
authors: Martina
authors: M
authors: Teichert
authors: M Arfan
authors: MA
authors: Ikram
authors: Thomas H
authors: TH
authors: Mosley
authors: Steve
authors: S
authors: Bevan
authors: Martin
authors: M
authors: Dichgans
authors: Peter M
authors: PM
authors: Rothwell
authors: Cathie L M
authors: CL
authors: Sudlow
authors: Jemma C
authors: JC
authors: Hopewell
authors: John C
authors: JC
authors: Chambers
authors: Danish
authors: D
authors: Saleheen
authors: Jaspal S
authors: JS
authors: Kooner
authors: John
authors: J
authors: Danesh
authors: Christopher P
authors: CP
authors: Nelson
authors: Jeanette
authors: J
authors: Erdmann
authors: Muredach P
authors: MP
authors: Reilly
authors: Sekar
authors: S
authors: Kathiresan
authors: Heribert
authors: H
authors: Schunkert
authors: Pierre-Emmanuel
authors: PE
authors: Morange
authors: Luigi
authors: L
authors: Ferrucci
authors: Johan G
authors: JG
authors: Eriksson
authors: David
authors: D
authors: Jacobs
authors: Ian J
authors: IJ
authors: Deary
authors: Nicole
authors: N
authors: Soranzo
authors: Jacqueline C M
authors: JC
authors: Witteman
authors: Eco J C
authors: EJ
authors: de Geus
authors: Russell P
authors: RP
authors: Tracy
authors: Caroline
authors: C
authors: Hayward
authors: Wolfgang
authors: W
authors: Koenig
authors: Francesco
authors: F
authors: Cucca
authors: J Wouter
authors: JW
authors: Jukema
authors: Per
authors: P
authors: Eriksson
authors: Sudha
authors: S
authors: Seshadri
authors: Hugh S
authors: HS
authors: Markus
authors: Hugh
authors: H
authors: Watkins
authors: Nilesh J
authors: NJ
authors: Samani
authors: Henri
authors: H
authors: Wallaschofski
authors: Nicholas L
authors: NL
authors: Smith
authors: David
authors: D
authors: Tregouet
authors: Paul M
authors: PM
authors: Ridker
authors: Weihong
authors: W
authors: Tang
authors: David P
authors: DP
authors: Strachan
authors: Anders
authors: A
authors: Hamsten
authors: Christopher J
authors: CJ
authors: O'Donnell
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D044383:Black People / Q000235:genetics / Q000706:statistics & numerical data; D002318:Cardiovascular Diseases / Q000208:ethnology* / Q000235:genetics* / Q000378:metabolism; D003324:Coronary Artery Disease / Q000208:ethnology / Q000235:genetics / Q000378:metabolism; D005260:Female; D005340:Fibrinogen / Q000235:genetics* / Q000378:metabolism*; D056426:Genetic Loci / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000208:ethnology; D055106:Genome-Wide Association Study; D006630:Hispanic or Latino / Q000235:genetics / Q000706:statistics & numerical data; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000208:ethnology / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D020521:Stroke / Q000208:ethnology / Q000235:genetics / Q000378:metabolism; D054556:Venous Thromboembolism / Q000208:ethnology / Q000235:genetics / Q000378:metabolism; D044465:White People / Q000235:genetics / Q000706:statistics & numerical data; D055815:Young Adult
chemical_list: D005340:Fibrinogen
keywords: cardiovascular diseases; fibrinogen; gene expression; genome-wide association study
references: Circulation. 2000 Apr 4;101(13):1546-51
references: 10747348
references: Circ Cardiovasc Genet. 2009 Apr;2(2):125-33
references: 20031576
references: Acta Haematol. 1957 Apr;17(4):237-46
references: 13434757
references: Am J Epidemiol. 2007 Oct 15;166(8):867-79
references: 17785713
references: PLoS One. 2011;6(9):e25581
references: 21980494
references: Thromb Haemost. 1994 Jun;71(6):719-22
references: 7974338
references: Nat Genet. 2011 Mar 06;43(4):339-44
references: 21378988
references: JAMA. 2005 Oct 12;294(14):1799-809
references: 16219884
references: Circ Cardiovasc Genet. 2010 Aug;3(4):365-73
references: 20562444
references: Circulation. 2011 Feb 22;123(7):731-8
references: 21300955
references: PLoS Genet. 2011 May;7(5):e1002078
references: 21637794
references: Lancet. 2001 Jan 13;357(9250):101-5
references: 11197396
references: Circ Cardiovasc Genet. 2009 Apr;2(2):134-41
references: 20031577
references: Genome Res. 2011 Jul;21(7):1008-16
references: 21602305
references: Br Heart J. 1993 Apr;69(4):338-42
references: 8489866
references: PLoS Genet. 2007 Jul;3(7):e114
references: 17676998
references: Arterioscler Thromb Vasc Biol. 2005 Oct;25(10):2228-33
references: 16123313
references: Nat Genet. 2012 Feb 05;44(3):328-33
references: 22306652
references: N Engl J Med. 1984 Aug 23;311(8):501-5
references: 6749207
references: Nat Genet. 2009 Dec;41(12):1313-8
references: 19898481
references: Ann Intern Med. 1993 Jun 15;118(12):956-63
references: 8489110
references: N Engl J Med. 2009 Apr 23;360(17):1718-28
references: 19369658
references: Genet Epidemiol. 2010 Dec;34(8):816-34
references: 21058334
references: Blood. 2005 Dec 15;106(13):4176-83
references: 16144795
references: Pharmacogenomics J. 2013 Feb;13(1):12-20
references: 22006096
references: Nat Genet. 2011 Jun;43(6):519-25
references: 21552263
references: Am Heart J. 2003 Mar;145(3):467-74
references: 12660670
references: BMJ. 1991 Sep 14;303(6803):605-9
references: 1932900
references: Nat Genet. 2011 Mar 06;43(4):333-8
references: 21378990
references: Bioinformatics. 2010 Sep 1;26(17):2190-1
references: 20616382
references: JAMA. 1987 Sep 4;258(9):1183-6
references: 3626001
references: PLoS Genet. 2010 Aug 12;6(8):
references: 20714348
references: Circ Cardiovasc Genet. 2010 Oct;3(5):475-83
references: 20923989
references: Int J Epidemiol. 2006 Aug;35(4):935-43
references: 16870675
references: PLoS Genet. 2009 Jun;5(6):e1000534
references: 19557189
references: Nat Genet. 2007 Jul;39(7):906-13
references: 17572673
references: Eur J Clin Invest. 1994 Jul;24(7):444-53
references: 7957500
references: Blood. 2009 May 21;113(21):5298-303
references: 19278955
references: PLoS Biol. 2008 May 6;6(5):e107
references: 18462017