Genome-wide association studies identify genetic loci for low von Willebrand factor levels

Eur J Hum Genet. 2016 Jul;24(7):1035-40. doi: 10.1038/ejhg.2015.222. Epub 2015 Oct 21.

Abstract

Low von Willebrand factor (VWF) levels are associated with bleeding symptoms and are a diagnostic criterion for von Willebrand disease, the most common inherited bleeding disorder. To date, it is unclear which genetic loci are associated with reduced VWF levels. Therefore, we conducted a meta-analysis of genome-wide association studies to identify genetic loci associated with low VWF levels. For this meta-analysis, we included 31 149 participants of European ancestry from 11 community-based studies. From all participants, VWF antigen (VWF:Ag) measurements and genome-wide single-nucleotide polymorphism (SNP) scans were available. Each study conducted analyses using logistic regression of SNPs on dichotomized VWF:Ag measures (lowest 5% for blood group O and non-O) with an additive genetic model adjusted for age and sex. An inverse-variance weighted meta-analysis was performed for VWF:Ag levels. A total of 97 SNPs exceeded the genome-wide significance threshold of 5 × 10(-8) and comprised five loci on four different chromosomes: 6q24 (smallest P-value 5.8 × 10(-10)), 9q34 (2.4 × 10(-64)), 12p13 (5.3 × 10(-22)), 12q23 (1.2 × 10(-8)) and 13q13 (2.6 × 10(-8)). All loci were within or close to genes, including STXBP5 (Syntaxin Binding Protein 5) (6q24), STAB5 (stabilin-5) (12q23), ABO (9q34), VWF (12p13) and UFM1 (ubiquitin-fold modifier 1) (13q13). Of these, UFM1 has not been previously associated with VWF:Ag levels. Four genes that were previously associated with VWF levels (VWF, ABO, STXBP5 and STAB2) were also associated with low VWF levels, and, in addition, we identified a new gene, UFM1, that is associated with low VWF levels. These findings point to novel mechanisms for the occurrence of low VWF levels.

Publication types

  • Meta-Analysis

MeSH terms

  • ABO Blood-Group System / genetics
  • Aged
  • Aged, 80 and over
  • Female
  • Genetic Loci*
  • Genome-Wide Association Study
  • Humans
  • Male
  • Middle Aged
  • Nerve Tissue Proteins / genetics
  • Polymorphism, Single Nucleotide
  • Proteins / genetics*
  • R-SNARE Proteins / genetics
  • White People / genetics
  • von Willebrand Diseases / blood
  • von Willebrand Diseases / genetics*
  • von Willebrand Factor / genetics
  • von Willebrand Factor / metabolism*

Substances

  • ABO Blood-Group System
  • Nerve Tissue Proteins
  • Proteins
  • R-SNARE Proteins
  • STXBP5 protein, human
  • UFM1 protein, human
  • Von Willebrand antigen
  • von Willebrand Factor