FGL1 as a modulator of plasma D‐dimer levels: Exome‐wide marker analysis of plasma tPA, PAI‐1, and D‐dimer

Background Use of targeted exome‐arrays with common, rare variants and functionally enriched variation has led to discovery of new genes contributing to population variation in risk factors. Plasminogen activator‐inhibitor 1 (PAI‐1), tissue plasminogen activator (tPA), and the plasma product D‐dimer are important components of the fibrinolytic system. There have been few large‐scale genome‐wide or exome‐wide studies of PAI‐1, tPA, and D‐dimer. Objectives We sought to discover new genetic loci contributing to variation in these traits using an exome‐array approach. Methods Cohort‐level analyses and fixed effects meta‐analyses of PAI‐1 (n = 15 603), tPA (n = 6876,) and D‐dimer (n = 19 306) from 12 cohorts of European ancestry with diverse study design were conducted, including single‐variant analyses and gene‐based burden testing. Results Five variants located in NME7, FGL1, and the fibrinogen locus, all associated with D‐dimer levels, achieved genome‐wide significance (P