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Genome-wide meta-analysis identifies 93 risk loci and enables risk prediction equivalent to monogenic forms of venous thromboembolism.
Ghouse, Jonas; Tragante, Vinicius; Ahlberg, Gustav; Rand, Søren A; Jespersen, Jakob B; Leinøe, Eva Birgitte; Vissing, Christoffer Rasmus; Trudsø, Linea; Jonsdottir, Ingileif; Banasik, Karina; Brunak, Søren; Ostrowski, Sisse R; Pedersen, Ole B; Sørensen, Erik; Erikstrup, Christian; Bruun, Mie Topholm; Nielsen, Kaspar Rene; Køber, Lars; Christensen, Alex H; Iversen, Kasper; Jones, David; Knowlton, Kirk U; Nadauld, Lincoln; Halldorsson, Gisli H; Ferkingstad, Egil; Olafsson, Isleifur; Gretarsdottir, Solveig; Onundarson, Pall T; Sulem, Patrick; Thorsteinsdottir, Unnur; Thorgeirsson, Gudmundur; Gudbjartsson, Daniel F; Stefansson, Kari; Holm, Hilma; Olesen, Morten Salling; Bundgaard, Henning.
Afiliación
  • Ghouse J; Laboratory for Molecular Cardiology, Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. jonas.ghouse@sund.ku.dk.
  • Tragante V; Laboratory for Molecular Cardiology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark. jonas.ghouse@sund.ku.dk.
  • Ahlberg G; deCODE genetics/Amgen, Inc., Reykjavik, Iceland.
  • Rand SA; Laboratory for Molecular Cardiology, Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
  • Jespersen JB; Laboratory for Molecular Cardiology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Leinøe EB; Laboratory for Molecular Cardiology, Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
  • Vissing CR; Laboratory for Molecular Cardiology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Trudsø L; Laboratory for Molecular Cardiology, Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
  • Jonsdottir I; Laboratory for Molecular Cardiology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Banasik K; Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
  • Brunak S; Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
  • Ostrowski SR; Laboratory for Molecular Cardiology, Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
  • Pedersen OB; Laboratory for Molecular Cardiology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Sørensen E; deCODE genetics/Amgen, Inc., Reykjavik, Iceland.
  • Erikstrup C; Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
  • Bruun MT; Iceland Department of Immunology, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland.
  • Nielsen KR; Translational Disease Systems Biology, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Køber L; Translational Disease Systems Biology, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Christensen AH; Department of Clinical Immunology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
  • Iversen K; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
  • Jones D; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
  • Knowlton KU; Department of Clinical Immunology, Næstved Hospital, Næstved, Denmark.
  • Nadauld L; Department of Clinical Immunology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
  • Halldorsson GH; Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark.
  • Ferkingstad E; Department of Clinical Immunology, Odense University Hospital, Odense, Denmark.
  • Olafsson I; Department of Clinical Immunology, Aalborg University Hospital, Aalborg, Denmark.
  • Gretarsdottir S; Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
  • Onundarson PT; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
  • Sulem P; Department of Cardiology, Copenhagen University Hospital, Herlev-Gentofte Hospital, Herlev, Denmark.
  • Thorsteinsdottir U; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
  • Thorgeirsson G; Department of Cardiology, Copenhagen University Hospital, Herlev-Gentofte Hospital, Herlev, Denmark.
  • Gudbjartsson DF; Precision Genomics, Intermountain Healthcare, Saint George, UT, USA.
  • Stefansson K; Intermountain Medical Center, Intermountain Heart Institute, Salt Lake City, UT, USA.
  • Holm H; University of Utah, School of Medicine, Salt Lake City, UT, USA.
  • Olesen MS; Precision Genomics, Intermountain Healthcare, Saint George, UT, USA.
  • Bundgaard H; Stanford University, School of Medicine, Stanford, CA, USA.
Nat Genet ; 55(3): 399-409, 2023 03.
Article en En | MEDLINE | ID: mdl-36658437
We report a genome-wide association study of venous thromboembolism (VTE) incorporating 81,190 cases and 1,419,671 controls sampled from six cohorts. We identify 93 risk loci, of which 62 are previously unreported. Many of the identified risk loci are at genes encoding proteins with functions converging on the coagulation cascade or platelet function. A VTE polygenic risk score (PRS) enabled effective identification of both high- and low-risk individuals. Individuals within the top 0.1% of PRS distribution had a VTE risk similar to homozygous or compound heterozygous carriers of the variants G20210A (c.*97 G > A) in F2 and p.R534Q in F5. We also document that F2 and F5 mutation carriers in the bottom 10% of the PRS distribution had a risk similar to that of the general population. We further show that PRS improved individual risk prediction beyond that of genetic and clinical risk factors. We investigated the extent to which venous and arterial thrombosis share clinical risk factors using Mendelian randomization, finding that some risk factors for arterial thrombosis were directionally concordant with VTE risk (for example, body mass index and smoking) whereas others were discordant (for example, systolic blood pressure and triglyceride levels).
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Trombosis / Tromboembolia Venosa Tipo de estudio: Clinical_trials / Etiology_studies / Prognostic_studies / Risk_factors_studies / Systematic_reviews Límite: Humans Idioma: En Revista: Nat Genet Asunto de la revista: GENETICA MEDICA Año: 2023 Tipo del documento: Article País de afiliación: Dinamarca Pais de publicación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Trombosis / Tromboembolia Venosa Tipo de estudio: Clinical_trials / Etiology_studies / Prognostic_studies / Risk_factors_studies / Systematic_reviews Límite: Humans Idioma: En Revista: Nat Genet Asunto de la revista: GENETICA MEDICA Año: 2023 Tipo del documento: Article País de afiliación: Dinamarca Pais de publicación: Estados Unidos