title: Gene-centric association signals for haemostasis and thrombosis traits identified with the HumanCVD BeadChip.
abstract: Coagulation phenotypes show strong intercorrelations, affect cardiovascular disease risk and are influenced by genetic variants. The objective of this study was to search for novel genetic variants influencing the following coagulation phenotypes: factor VII levels, fibrinogen levels, plasma viscosity and platelet count. We genotyped the British Women's Heart and Health Study (n=3,445) and the Whitehall II study (n=5,059) using the Illumina HumanCVD BeadArray to investigate genetic associations and pleiotropy. In addition to previously reported associations (SH2B3, F7/F10, PROCR, GCKR, FGA/FGB/FGG, IL5), we identified novel associations at GRK5 (rs10128498, p=1.30x10(-6)), GCKR (rs1260326, p=1.63x10(-6)), ZNF259-APOA5 (rs651821, p=7.17x10(-6)) with plasma viscosity; and at CSF1 (rs333948, p=8.88x10(-6)) with platelet count. A pleiotropic effect was identified in GCKR which associated with factor VII (p=2.16x10(-7)) and plasma viscosity (p=1.63x10(-6)), and, to a lesser extent, ZNF259-APOA5 which also associated with factor VII and fibrinogen (p<1.00x10-²) and plasma viscosity (p<1.00x10(-5)). Triglyceride associated variants were overrepresented in factor VII and plasma viscosity associations. Adjusting for triglyceride levels resulted in attenuation of associations at the GCKR and ZNF259-APOA5 loci. In addition to confirming previously reported associations, we identified four single nucleotide polymorphisms (SNPs) associated with plasma viscosity and platelet count and found evidence of pleiotropic effects with SNPs in GCKR and ZNF259-APOA5. These triglyceride-associated, pleiotropic SNPs suggest a possible causal role for triglycerides in coagulation.
authors.affiliation: MRC Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.
authors.forename: Tom R
authors.initials: TR
authors.lastname: Gaunt
authors.affiliation: University College London Genetics Institute, Department of Genetics, Environment and Evolution, Gower St, London WC1E 6BT, UK.
authors.forename: Delilah
authors.initials: D
authors.lastname: Zabaneh
authors.affiliation: University College London Genetics Institute, Department of Genetics, Environment and Evolution, Gower St, London WC1E 6BT, UK.
authors.forename: Sonia
authors.initials: S
authors.lastname: Shah
authors.affiliation: MRC Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Guyatt
authors.affiliation: MRC Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.
authors.forename: Christophe
authors.initials: C
authors.lastname: Ladroue
authors.affiliation: Genetic Epidemiology Group, Department of Epidemiology and Public Health, University College London, 1-19 Torrington Street, London WC1E 6BT, UK.
authors.forename: Meena
authors.initials: M
authors.lastname: Kumari
authors.affiliation: Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, 5 University St, London WC1E 6JF, UK.
authors.forename: Fotios
authors.initials: F
authors.lastname: Drenos
authors.affiliation: Genetic Epidemiology Group, Department of Epidemiology and Public Health, University College London, 1-19 Torrington Street, London WC1E 6BT, UK.
authors.forename: Tina
authors.initials: T
authors.lastname: Shah
authors.affiliation: Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, 5 University St, London WC1E 6JF, UK.
authors.forename: Philippa J
authors.initials: PJ
authors.lastname: Talmud
authors.affiliation: Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.|Institute of Cardiovascular Science, University College London, Gower Street, London, WC1E 6BT, UK.
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Casas
authors.affiliation: Institute of Cardiovascular & Medical Sciences, Room 335, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow, G12 8TA, UK.
authors.forename: Gordon
authors.initials: G
authors.lastname: Lowe
authors.affiliation: Institute of Cardiovascular & Medical Sciences, Room 335, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow, G12 8TA, UK.
authors.forename: Ann
authors.initials: A
authors.lastname: Rumley
authors.affiliation: MRC Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.
authors.forename: Debbie A
authors.initials: DA
authors.lastname: Lawlor
authors.affiliation: Genetic Epidemiology Group, Department of Epidemiology and Public Health, University College London, 1-19 Torrington Street, London WC1E 6BT, UK.
authors.forename: Mika
authors.initials: M
authors.lastname: Kivimaki
authors.affiliation: Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.|Quantitative Sciences, GlaxoSmithKline, Stevenage, UK.
authors.forename: John
authors.initials: J
authors.lastname: Whittaker
authors.affiliation: Genetic Epidemiology Group, Department of Epidemiology and Public Health, University College London, 1-19 Torrington Street, London WC1E 6BT, UK.
authors.forename: Aroon D
authors.initials: AD
authors.lastname: Hingorani
authors.affiliation: University College London Genetics Institute, Department of Genetics, Environment and Evolution, Gower St, London WC1E 6BT, UK.|Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, 5 University St, London WC1E 6JF, UK.
authors.forename: Steve E
authors.initials: SE
authors.lastname: Humphries
authors.affiliation: MRC Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.
authors.forename: Ian N
authors.initials: IN
authors.lastname: Day
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000072040:Apolipoprotein A-V; D001054:Apolipoproteins A / Q000235:genetics; D001792:Blood Platelets / Q000473:pathology*; D001809:Blood Viscosity / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D002452:Cell Count; D004252:DNA Mutational Analysis; D005167:Factor VII / Q000235:genetics / Q000378:metabolism*; D005340:Fibrinogen / Q000235:genetics / Q000378:metabolism*; D054774:G-Protein-Coupled Receptor Kinase 5 / Q000235:genetics; D056726:Genetic Association Studies; D006487:Hemostasis / Q000235:genetics*; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics; D026901:Membrane Transport Proteins; D046228:Microarray Analysis; D008863:Microspheres; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D019655:Quantitative Trait, Heritable; D013927:Thrombosis / Q000235:genetics*
chemical_list: C437704:APOA5 protein, human; D048868:Adaptor Proteins, Signal Transducing; D000072040:Apolipoprotein A-V; D001054:Apolipoproteins A; D002352:Carrier Proteins; C485100:GCKR protein, human; D026901:Membrane Transport Proteins; C099746:ZPR1 protein, human; D016173:Macrophage Colony-Stimulating Factor; D005167:Factor VII; D005340:Fibrinogen; D054774:G-Protein-Coupled Receptor Kinase 5; C517898:GRK5 protein, human
keywords: Haemostasis; HumanCVD; clotting factors; genetic association; thrombosis