Genome-wide meta-analysis identifies 93 risk loci and enables risk prediction equivalent to monogenic forms of venous thromboembolism

Research output: Contribution to journalJournal articleResearchpeer-review

  • Vinicius Tragante
  • Gustav Ahlberg
  • Søren A Rand
  • Jakob B Jespersen
  • Eva Birgitte Leinøe
  • Christoffer Rasmus Vissing
  • Linea Trudsø
  • Ingileif Jonsdottir
  • Erik Sørensen
  • Christian Erikstrup
  • Mie Topholm Bruun
  • Kaspar Rene Nielsen
  • Alex H. Christensen
  • David Jones
  • Kirk U Knowlton
  • Lincoln Nadauld
  • Gisli H Halldorsson
  • Egil Ferkingstad
  • Isleifur Olafsson
  • Solveig Gretarsdottir
  • Pall T Onundarson
  • Patrick Sulem
  • Unnur Thorsteinsdottir
  • Gudmundur Thorgeirsson
  • Daniel F Gudbjartsson
  • Kari Stefansson
  • Hilma Holm

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).

Original languageEnglish
JournalNature Genetics
Pages (from-to)399-409
Number of pages18
Publication statusPublished - 2023

Bibliographical note

© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.

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