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

Jonas Ghouse*, Vinicius Tragante, Gustav Ahlberg, Søren A. Rand, Jakob B. Jespersen, Eva Birgitte Leinøe, Christoffer Rasmus Vissing, Linea Trudsø, Ingileif Jonsdottir, Karina Banasik, Søren Brunak, Sisse R. Ostrowski, Ole B. Pedersen, Erik Sørensen, Christian Erikstrup, Mie Topholm Bruun, Kaspar Rene Nielsen, Lars Køber, Alex H. Christensen, Kasper IversenDavid 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, Morten Salling Olesen, Henning Bundgaard

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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
Pages (from-to)399-409
Number of pages11
JournalNature Genetics
Volume55
Issue number3
DOIs
Publication statusPublished - Mar 2023

Bibliographical note

Funding Information:
This research has been conducted using the UKB resource under application no. 43247. This work was supported by BRIDGE—Translational Excellence Programme (nos. NNF18SA0034956 and NNF20SA0064340), The John and Birthe Meyer Foundation, The Innovation Fund Denmark (PM Heart), NordForsk, Villadsen Family Foundation, The Arvid Nilsson Foundation, The Hallas-Møller Emerging Investigator Novo Nordisk (no. NNF17OC0031204) and Novo Nordisk Foundation (nos. NNF17OC0027594 and NNF14CC0001). All human research was approved within each contributing study by the relevant institutional review board (CHB-CVDC/DBDS: National Committee on Health Research Ethics; deCODE: National Bioethics Committee; Intermountain Healthcare: Intermountain Healthcare Institutional Review Board; UKB: Northwest Multicenter Research Ethics Committee; FinnGen: The Coordinating Ethics Committee of the Hospital District of Helsinki and Uusimaa; MVP: VA Central Institutional Review Board) and conducted according to the Declaration of Helsinki. All participants (except for CHB-CVDC) provided written informed consent. For CHB-CVDC, patients were informed about the opt-out possibility of having their biological specimens excluded from use in research in general. Since 2004, a national Register on Tissue Application (Vævsanvendelsesregistret) lists all individuals who have chosen to opt out and whose samples cannot be used for research purposes. Before initiating this study, individuals listed in the Register on Tissue Application were excluded. Additional information is provided in the .

Funding Information:
This research has been conducted using the UKB resource under application no. 43247. This work was supported by BRIDGE—Translational Excellence Programme (nos. NNF18SA0034956 and NNF20SA0064340), The John and Birthe Meyer Foundation, The Innovation Fund Denmark (PM Heart), NordForsk, Villadsen Family Foundation, The Arvid Nilsson Foundation, The Hallas-Møller Emerging Investigator Novo Nordisk (no. NNF17OC0031204) and Novo Nordisk Foundation (nos. NNF17OC0027594 and NNF14CC0001). All human research was approved within each contributing study by the relevant institutional review board (CHB-CVDC/DBDS: National Committee on Health Research Ethics; deCODE: National Bioethics Committee; Intermountain Healthcare: Intermountain Healthcare Institutional Review Board; UKB: Northwest Multicenter Research Ethics Committee; FinnGen: The Coordinating Ethics Committee of the Hospital District of Helsinki and Uusimaa; MVP: VA Central Institutional Review Board) and conducted according to the Declaration of Helsinki. All participants (except for CHB-CVDC) provided written informed consent. For CHB-CVDC, patients were informed about the opt-out possibility of having their biological specimens excluded from use in research in general. Since 2004, a national Register on Tissue Application (Vævsanvendelsesregistret) lists all individuals who have chosen to opt out and whose samples cannot be used for research purposes. Before initiating this study, individuals listed in the Register on Tissue Application were excluded. Additional information is provided in the Supplementary Note.

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

Other keywords

  • Humans
  • Venous Thromboembolism/genetics
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
  • Risk Factors
  • Thrombosis

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