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

J Van Loon, A Dehghan, T Weihong… - European Journal of …, 2016 - nature.com
J Van Loon, A Dehghan, T Weihong, S Trompet, WL McArdle, FFW Asselbergs, MH Chen
European Journal of Human Genetics, 2016nature.com
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 …
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.
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