Background: Multi-phenotype analysis of genetically correlated phenotypes can increase the statistical power to detect loci associated with multiple traits, leading to the discovery of novel loci. This is the first study to date to comprehensively analyze the shared genetic effects within different hemostatic traits, and between these and their associated disease outcomes.
Objectives:To discover novel genetic associations by combining summary data of correlated hemostatic traits and disease events. Methods: Summary statistics from genome wide-association studies (GWAS) from seven hemostatic traits (factor VII [FVII], factor VIII [FVIII], von Willebrand factor [VWF] factor XI [FXI], fibrinogen, tissue plasminogen activator [tPA], plasminogen activator inhibitor 1 [PAI-1]) and three major cardiovascular (CV) events (venous thromboembolism [VTE], coronary artery disease [CAD], ischemic stroke [IS]), wereThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Genome-wide association studies (GWAS) have identified dozens of loci underlying the variability of plasma levels for individual hemostatic traits. [1][2][3][4][5][6][7][8] Further, GWAS for venous thromboembolism (VTE), 9,10 coronary artery disease (CAD) [11][12][13] and ischemic stroke (IS), 11,14 have discovered 34, 169, and 20 genetic risk loci associated with these cardiovascular (CV) events, respectively.Results from GWAS indicate that several of these hemostatic traits are genetically correlated with each other, sharing genetic loci that regulate their plasma levels. 1,[4][5][6][7][8] There are also shared genetic loci between hemostatic traits and CV events, again suggesting common regulators and possibly a causal pathway between the hemostatic trait and the CV event. 4,[7][8][9]12,14 The common regulatory loci between traits-even if the traits are not causally associated with each other-can be used to advance discovery of novel genetic loci common to the traits. This discovery can be accomplished with multiphenotype methods that incorporate summary statistics from several GWAS, increasing the statistical power to detect loci affecting two or more phenotypes by increasing the effective sample size. [15][16][17] In the present study, we used summary statistics of published GWAS from 7 hemostatic traits (FVII, FVIII, VWF, FXI, fibrinogen, PAI-1, tPA), and 3 CV events (VTE, CAD, IS) to calculate their genetic correlations and to conduct multi-phenotype meta-analyses to detect new genetic loci not previously known to be associated with these phenotypes.