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Multi-phenotype Analysis of Hemostatic Factors with Venous Thromboembolism Reveals Novel Genetic Associations

1Research institute of Hospital de Sant Pau, Barcelona, Spain, 2Human Genetics Center, Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, The University of Texas Health Sciences Center, Houston, United States, 3Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States, 4Corporal Michael Crescenz VA Medical Center, Philadelphia, United States, 5Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States, 6Department of Epidemiology, University of Washington, Seattle, United States, 7Kaiser Permanente Washington Research Institute, Kaiser Permanente Washington, Seattle, United States, 8Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development, Seattle, United States

Abstract Number: OC 19.1

Meeting: ISTH 2021 Congress

Theme: Venous Thromboembolism » Genetic Risk Factors of Thrombosis

Background: Previous work meta-analyzing genetically correlated phenotypes have suggested an increase in statistical power, allowing for the detection of novel associations and identifying new associated loci that are common to the studied phenotypes.

Aims: To use summary statistics from European-ancestry genome-wide association study (GWAS) meta-analyses of 7 hemostatic factors, previously published by the CHARGE Consortium: fibrinogen (n=120,246), FVII (n=15,795), FVIII (n=32,610), VWF (n=46,354), tPA (n=26,929), PAI-1 (n=19,599) and FXI (n=16,169), and combine them in multi-phenotype analyses with venous thromboembolism (VTE, 30,234 cases) from the INVENT Consortium GWAS.

Methods: Heritabilities and genetic correlations from each phenotype and each pair of hemostasis-VTE phenotypes, respectively, were calculated using LDSC (Linkage Disequilibrium Score Regression) software. Each hemostatic factor was meta-analyzed with the European-ancestry summary statistics of VTE GWAS meta-analysis using the metaUSAT R package.

Results: Among the analyzed coagulation factors, FVIII and VWF showed the strongest correlations with VTE (0.23 and 0.27, respectively). The joint analyses of each coagulation factor with VTE revealed increased power to detect associated variants not detected in the individual analyses. In FVII-VTE multi-phenotype analysis, two novel associations reached genome-wide significance (P-value < 2.5 · 10-8, variants rs3796159 and rs6821496) located at XXYLT1 and SCD5 genes. Similarly, the FVIII-VTE multi-phenotype analysis detected two significant variants (rs710446 and rs35257264) at KNG1 and KIRREL3 genes that were not genome-wide significant in the individual datasets but that have been associated to VTE and FVIII in candidate genes studies. In the fibrinogen-VTE analysis, two novel associations were found (rs6430552 and rs10859534) at ACMSD and SOCS2 genes.

Conclusions: Applying multi-phenotype methods on genetically correlated traits allows an increase in the statistical power to detect common associations. The analyses of multiple pairs of coagulation factors with VTE outcome has revealed novel associations that are regulating coagulation factor’ levels and risk of thrombosis.

To cite this abstract in AMA style:

Temprano-Sagrera G, S de Vries P, Martín-Bórnez M, M Damrauer S, L Smith N, Sabater-Lleal M, o. Multi-phenotype Analysis of Hemostatic Factors with Venous Thromboembolism Reveals Novel Genetic Associations [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/multi-phenotype-analysis-of-hemostatic-factors-with-venous-thromboembolism-reveals-novel-genetic-associations/. Accessed June 25, 2022.

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