Genetic determinants of low von Willebrand factor from whole exome sequencing

Abstract

Low von Willebrand factor (VWF; 30–50 IU/dL) is a common clinical phenotype associated with bleeding, but its genetic basis remains poorly defined. We aimed to explore the contribution of rare and common variants to Low VWF and bleeding risk. Whole-exome sequencing was performed in 115 Low VWF cases (33 years, range 18–72) and 139 controls (39 years, range 18–65). Common variant association, gene burden, gene-set burden, and PRS analyses were performed. Only 29 cases (25%) carried known or predicted pathogenic VWF variants. Cases showed a significantly higher burden of rare VWF variants (gnomAD-MAF < 0.01) compared with controls (p = 4.47×10⁻⁶), with no difference in common variant burden. Notably, in cases, the burden of rare VWF variants inversely correlated with VWF:activity (p = 0.007) and VWF:Ag (p = 0.046), indicating that cumulative rare coding variants quantitatively lower VWF plasma levels. Beyond VWF, we investigated loci previously implicated by GWAS and rare/low frequent variants (MAF < 0.05) in ABO and NIPSNAP3B were associated with VWF levels (burden test p = 0.00065 and p = 0.0039), with additional borderline signals in RAB5C, KAT2A, and ACE (p ≤0.087). Among common variants (gnomAD-MAF > 0.05), 27 variants reached nominal statistical significance in 8 genes (ABO, VWF, PXK, OR13C5, STAB2, GIMAP7, TNPO1, SCARA5). Bleeding severity (ISTH-BAT) was significantly associated with the burden of common variants in previously identified GWAS loci (p = 0.0312). This relationship was further supported by a PRS analysis (p = 0.0434). Together, these findings support that Low VWF reflects both the cumulative effect of rare VWF variants and a broader polygenic background involving VWF and non-VWF loci, with common non-VWF variants contributing to the bleeding tendency. Von Willebrand factor (VWF) is a blood protein that helps stop bleeding. Some people have reduced levels of VWF (30–50 IU/dL), known as Low VWF, which can lead to significant bleeding. However, the genetic causes and variability in bleeding symptoms are not fully understood. We analyzed genetic data from 115 individuals with Low VWF and 139 healthy controls using whole-exome sequencing to investigate the role of both rare and common genetic variants. Most patients did not carry a single clearly disease-causing mutation in the VWF gene but instead had a higher burden of rare variants associated with lower VWF levels. We also identified additional genes influencing VWF regulation. Moreover, a higher burden of common risk variants was linked to more severe bleeding. These findings suggest that Low VWF is driven by combined effects of rare and common genetic variation. Seidizadeh et al. performed whole-exome sequencing in 115 Low VWF cases and 139 controls to examine the genetic architecture of low VWF levels and bleeding risk. They show that rare VWF variants, common VWF and non-VWF modifiers, and polygenic factors jointly influence VWF levels and bleeding risk, supporting a continuum model of VWF regulation.