title: A genome-wide association study for venous thromboembolism: the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium.
abstract: Venous thromboembolism (VTE) is a common, heritable disease resulting in high rates of hospitalization and mortality. Yet few associations between VTE and genetic variants, all in the coagulation pathway, have been established. To identify additional genetic determinants of VTE, we conducted a two-stage genome-wide association study (GWAS) among individuals of European ancestry in the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) VTE consortium. The discovery GWAS comprised 1,618 incident VTE cases out of 44,499 participants from six community-based studies. Genotypes for genome-wide single-nucleotide polymorphisms (SNPs) were imputed to approximately 2.5 million SNPs in HapMap and association with VTE assessed using study-design appropriate regression methods. Meta-analysis of these results identified two known loci, in F5 and ABO. Top 1,047 tag SNPs (P ≤ 0.0016) from the discovery GWAS were tested for association in an additional 3,231 cases and 3,536 controls from three case-control studies. In the combined data from these two stages, additional genome-wide significant associations were observed on 4q35 at F11 (top SNP rs4253399, intronic to F11) and on 4q28 at FGG (rs6536024, 9.7 kb from FGG; P < 5.0 × 10(-13) for both). The associations at the FGG locus were not completely explained by previously reported variants. Loci at or near SUSD1 and OTUD7A showed borderline yet novel associations (P < 5.0 × 10(-6) ) and constitute new candidate genes. In conclusion, this large GWAS replicated key genetic associations in F5 and ABO, and confirmed the importance of F11 and FGG loci for VTE. Future studies are warranted to better characterize the associations with F11 and FGG and to replicate the new candidate associations.
authors: Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA.
authors: Weihong
authors: W
authors: Tang
authors: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.|Scientific Institute Dutch Pharmacists, The Hague, The Netherlands.
authors: Martina
authors: M
authors: Teichert
authors: Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
authors: Daniel I
authors: DI
authors: Chasman
authors: Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic, Rochester, MN, USA.
authors: John A
authors: JA
authors: Heit
authors: INSERM UMR_S 1062; Université de la Méditerranée, Marseille, France.
authors: Pierre-Emmanuel
authors: PE
authors: Morange
authors: Department of Medicine, University of Washington, Seattle, WA, USA.
authors: Guo
authors: G
authors: Li
authors: Department of Lab Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
authors: Nathan
authors: N
authors: Pankratz
authors: Department of Haematology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Frank W
authors: FW
authors: Leebeek
authors: Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, L8S4K1, Canada.
authors: Guillaume
authors: G
authors: Paré
authors: Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors: Mariza
authors: M
authors: de Andrade
authors: University of Bordeaux, U708, F-33000, Bordeaux, France.
authors: Christophe
authors: C
authors: Tzourio
authors: Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, WA, USA.|Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA.
authors: Bruce M
authors: BM
authors: Psaty
authors: Division of Biostatistics, University of Minnesota, Minneapolis, MN, USA.
authors: Saonli
authors: S
authors: Basu
authors: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Rikje
authors: R
authors: Ruiter
authors: Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors: Lynda
authors: L
authors: Rose
authors: Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors: Sebastian M
authors: SM
authors: Armasu
authors: Department of Statistics, University of Aukland, Aukland, NZ.
authors: Thomas
authors: T
authors: Lumley
authors: Department of Epidemiology, University of Washington, Seattle, WA, USA.|Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA.|Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA.
authors: Susan R
authors: SR
authors: Heckbert
authors: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.|Netherlands Consortium for Healthy Aging, Rotterdam, The Netherlands.|Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: André G
authors: AG
authors: Uitterlinden
authors: Commissariat à l'Energie Atomique, Institut de Génomique, Centre National de Génotypage, F-91057, Evry, France.
authors: Mark
authors: M
authors: Lathrop
authors: Department of Biostatistics, University of Washington, Seattle, WA, USA.
authors: Kenneth M
authors: KM
authors: Rice
authors: Departments of Medicine and Pathology, University of Vermont, Burlington, Vermont, USA.
authors: Mary
authors: M
authors: Cushman
authors: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Albert
authors: A
authors: Hofman
authors: INSERM, UMR_S 744, Institut Pasteur de Lille; Université de Lille Nord de France, F-59019, Lille, France.
authors: Jean-Charles
authors: JC
authors: Lambert
authors: Department of Medicine, Boston University, Boston, MA, USA.
authors: Nicole L
authors: NL
authors: Glazer
authors: Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA.
authors: James S
authors: JS
authors: Pankow
authors: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Jacqueline C
authors: JC
authors: Witteman
authors: INSERM, UMR_S 744, Institut Pasteur de Lille; Université de Lille Nord de France, F-59019, Lille, France.|Centre Hospitalier Régional Universitaire de Lille, F-59037, Lille, France.
authors: Philippe
authors: P
authors: Amouyel
authors: Department of Medicine, University of Washington, Seattle, WA, USA.
authors: Joshua C
authors: JC
authors: Bis
authors: Department of Pathology, University of Vermont, Burlington, VT, USA.
authors: Edwin G
authors: EG
authors: Bovill
authors: Division of Biostatistics, University of Minnesota, Minneapolis, MN, USA.
authors: Xiaoxiao
authors: X
authors: Kong
authors: Departments of Biochemistry and Pathology, University of Vermont, Burlington, VT, USA.
authors: Russell P
authors: RP
authors: Tracy
authors: Human Genetics Center and Human Genome Sequencing Center, University of Texas Health Science Center at Houston, Houston, Texas, USA.
authors: Eric
authors: E
authors: Boerwinkle
authors: Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: Jerome I
authors: JI
authors: Rotter
authors: INSERM, UMR_S 937, ICAN Institute for Cardiometabolism and Nutrition, University Pierre & Marie Curie, Paris 06, F-75013, Paris, France.
authors: David-Alexandre
authors: DA
authors: Trégouët
authors: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.|Drug Safety Unit, Inspectorate for Health Care, The Hague, the Netherlands.
authors: Daan W
authors: DW
authors: Loth
authors: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.|Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.|Drug Safety Unit, Inspectorate for Health Care, The Hague, the Netherlands.
authors: Bruno H Ch
authors: BHC
authors: Stricker
authors: Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
authors: Paul M
authors: PM
authors: Ridker
authors: Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA.
authors: Aaron R
authors: AR
authors: Folsom
authors: Department of Epidemiology, University of Washington, Seattle, WA, USA.|Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA.
authors: Nicholas L
authors: NL
authors: Smith
mesh_terms: D000368:Aged; D000375:Aging; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012044:Regression Analysis; D012307:Risk Factors; D054556:Venous Thromboembolism / Q000453:epidemiology / Q000235:genetics*
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