Meta-analysis of Genome-Wide-Association Sudies for plasma Factor XI. FXI GWAS meta-analysis

Coagulation factor XI (FXI) has become increasingly interesting for its role in pathogenesis of thrombosis. While elevated plasma levels of FXI have been associated with venous thromboembolism and ischemic stroke, its deficiency is associated with mild bleeding. We aimed to determine novel genetic and post-transcriptional plasma FXI regulators.We performed a genome-wide association study (GWAS) for plasma FXI levels, using novel data imputed to the 1000 Genomes reference panel. Individual GWAS analyses, including a total of 16,169 European individuals from the ARIC, GHS, MARTHA and PROCARDIS studies, were meta-analyzed and further replicated in 2,045 individuals from the F5L family, GAIT2 and MEGA studies. Three loci showed robust, replicating association with circulating FXI levels: KNG1 (rs710446, p-value=2.07x10-302), F11 (rs4253417, p-value=2.86x10-193), and a novel association in GCKR (rs780094, p-value=3.56x10-09), here for the first time implicated in FXI regulation. Conditional and haplotype analyses demonstrated a complex association signal, with additional novel SNPs modulating plasma FXI levels in both the F11 and KNG1 loci. These results should open the door to new therapeutic targets for thrombosis prevention.