VPB1045 - Transcriptome-wide Association Studies reveal novel genes regulating plasma levels of hemostatic factors

Background: Factor VIII (FVIII), von Willebrand factor (VWF), fibrinogen, antithrombin (AT), and protein C (PC) plasma levels are risk factors for venous thromboembolism (VTE). Genome-wide association studies (GWAS) have identified genetic variants associated with plasma levels of these factors. By integrating GWAS and transcript expression, transcriptome-wide association studies (TWAS) perform tests on biologically informed aggregates of variants, therefore reducing the multiple-testing penalty and increasing power to find candidate causal associated genes.

Aims: To explore associations between the genetic component of gene expression and plasma levels of FVIII, VWF, fibrinogen, AT, and PC.

Methods: We leveraged summary data for FVIII (n=42,125), VWF (n=44,808), fibrinogen (n=120,247), AT (n=25,243), and PC (n=19,285) from ongoing meta-analyses of GWAS within the CHARGE Hemostasis Working Group and performed TWAS analyses via SPrediXcan in mechanistically related tissues to identify gene expression regulating plasma levels of these proteins. We then applied fine-mapping and colocalization pipelines, using FOCUS and fastENLOC. Finally, TWAS-based gene set enrichment was analyzed via GIGSEA to discover the regulatory network underlying plasma levels of studied factors.

Results: Overall, we detected differentially expressed genes in 15 loci associated with FVIII levels, 13 loci with VWF levels, 50 loci with fibrinogen levels, 4 loci with AT levels, and 10 loci associated with PC levels. We also found colocalization evidence between GWAS signals and gene expression of TWAS-identified genes associated with FVIII (n=6), VWF (n=7), fibrinogen (n=45), AT (n=2), and PC (n=2). Of these loci, RARS2, PSMB5, and SEPT9 (FVIII), RASIP1 (VWF), PCNX3, IRF8, and PTPN2 (fibrinogen), FCGRT (AT), and RP11-13A1.1, and RP13-942N8.1 (PC) were novel associations not detected by the corresponding GWAS input.

Conclusion(s): TWAS-based approaches identified 10 novel significant loci associated with plasma levels of hemostatic factors, underlining the increased power to detect novel associations by integrating expression and genomic data.