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

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).

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Fig. 1: Effect size distribution and pleiotropic associations.
Fig. 2: Gene prioritization.
Fig. 3: Phenome-wide associations between PRSVTE and selected cardiometabolic traits, autoimmune disorders, malignancies and biomarkers in the UKB.
Fig. 4: PRSVTE and risk of VTE in the UKB.
Fig. 5: Ten-year risk of VTE according to PRS and clinical and genetic risk factors.

Data availability

GWAS meta-analysis summary statistics and GWAS summary statistics from CHB-CVDC/DBDS, Intermountain healthcare and deCODE are available at https://www.decode.com/summarydata. Data from the UKB samples are available through UKB (https://www.ukbiobank.ac.uk/). FinnGen GWAS summary statistics are publicly accessible following registration (https://www.finngen.fi/en/access_results). Data from MVP are publicly available through dbGAP, accession code phs001672.v2.p1. The VTE PRS is available at the PGS Catalog (PGS ID accession: PGS003332). Individual-level data sharing is subject to restrictions imposed by patient consent and local ethics review boards. The GTEx v.8 eQTL data used in this study are available in the GTEx Portal (https://gtexportal.org/home/datasets). MSigDB gene sets are available online (https://www.gsea-msigdb.org/gsea/msigdb/) and through FUMA (https://fuma.ctglab.nl/).

Code availability

The following software and packages were used for data analysis: PLINK v.2.0 (https://www.cog-genomics.org/plink/2.0/), METAL v.2011-03-25 (http://csg.sph.umich.edu/abecasis/Metal/download/), MAGMA v.1.07 (https://ctg.cncr.nl/software/magma), EasyQC v.9.2 (https://www.uni-regensburg.de/medizin/epidemiologie-praeventivmedizin/genetische-epidemiologie/software/), FUMA v.1.3.8 (https://fuma.ctglab.nl/), LD score regression v.1.0.1 (https://github.com/bulik/ldsc), PoPS v.0.1 (https://github.com/FinucaneLab/pops/tree/add-license-1), PRS–CS v.2021-06-04 (https://github.com/getian107/PRScs/), REGENIE v.2.0.1 (https://rgcgithub.github.io/regenie/), TwoSampleMR v.0.5.6 (https://mrcieu.github.io/TwoSampleMR/), MiXeR v.1.3.0 (https://github.com/precimed/mixer), BOLT-REML v.2.4 (https://alkesgroup.broadinstitute.org/BOLT-LMM/BOLT-LMM_manual.html) and R v.4.1.2 (https://www.r-project.org/).

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Acknowledgements

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.

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Contributions

J.G., V.T., H.H., M.S.O. and H.B. conceived the study. J.G., V.T., E.F., G.A., G.H.H., S.G. and D.F.G. performed analyses in the respective cohorts. H.H., D.F.G., P.S., U.T., M.S.O. and H.B. supervised analyses in their respective cohorts. J.G., V.T., G.A., H.H., M.S.O. and H.B. contributed to writing the manuscript. J.G. and V.T. performed meta-analysis and created figures and tables. J.G and V.T. performed downstream analyses and drafted the manuscript. S.A.R., J.B.J., E.B.L., C.R.V., L.T., I.J., K.B., S.B., S.R.O., O.B.P., E.S., C.E., M.T.B., K.R.N., L.K., A.H.C., K.I., D.J., K.U.K., L.N., I.O., P.T.O., G.T. and K.S. interpreted the results and reviewed and commented on the manuscript.

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Correspondence to Jonas Ghouse.

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The authors who are affiliated with deCODE genetics/Amgen Inc. declare competing interests as employees. H.B. receives lecture fees from Bristol-Myers Squibb and Merck Sharp and Dohme. S.B. is a board member for Proscion A/S and Intomics A/S. All other authors declare no competing interests.

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Ghouse, J., Tragante, V., Ahlberg, G. et al. Genome-wide meta-analysis identifies 93 risk loci and enables risk prediction equivalent to monogenic forms of venous thromboembolism. Nat Genet (2023). https://doi.org/10.1038/s41588-022-01286-7

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