TY - JOUR

T1 - Genome-wide meta-analysis identifies 93 risk loci and enables risk prediction equivalent to monogenic forms of venous thromboembolism

AU - Ghouse, Jonas

AU - Tragante, Vinicius

AU - Ahlberg, Gustav

AU - Rand, Søren A

AU - Jespersen, Jakob B

AU - Leinøe, Eva Birgitte

AU - Vissing, Christoffer Rasmus

AU - Trudsø, Linea

AU - Jonsdottir, Ingileif

AU - Banasik, Karina

AU - Brunak, Søren

AU - Ostrowski, Sisse R

AU - Pedersen, Ole B

AU - Sørensen, Erik

AU - Erikstrup, Christian

AU - Bruun, Mie Topholm

AU - Nielsen, Kaspar Rene

AU - Køber, Lars

AU - Christensen, Alex H.

AU - Iversen, Kasper

AU - Jones, David

AU - Knowlton, Kirk U

AU - Nadauld, Lincoln

AU - Halldorsson, Gisli H

AU - Ferkingstad, Egil

AU - Olafsson, Isleifur

AU - Gretarsdottir, Solveig

AU - Onundarson, Pall T

AU - Sulem, Patrick

AU - Thorsteinsdottir, Unnur

AU - Thorgeirsson, Gudmundur

AU - Gudbjartsson, Daniel F

AU - Stefansson, Kari

AU - Holm, Hilma

AU - Olesen, Morten Salling

AU - Bundgaard, Henning

N1 - © 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.

PY - 2023

Y1 - 2023

N2 - 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).

AB - 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).

U2 - 10.1038/s41588-022-01286-7

DO - 10.1038/s41588-022-01286-7

M3 - Journal article

C2 - 36658437

VL - 55

SP - 399

EP - 409

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

ER -