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

van Loon, J. et al. (2016) Genome-wide association studies identify genetic loci for low von Willebrand factor levels. European Journal of Human Genetics, 24(7), pp. 1035-1040. (doi: 10.1038/ejhg.2015.222) (PMID:26486471)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Strachan, Mr David and Stott J, Professor David and Rumley, Dr Ann and Lowe, Professor Gordon
Authors: van Loon, J., Dehghan, A., Weihong, T., Trompet, S., McArdle, W. L., Asselbergs, F. F.W., Chen, M.-H., Lopez, L. M., Huffman, J. E., Leebeek, F. W.G., Basu, S., Stott, D., Rumley, A., Gansevoort, R. T., Davies, G., Wilson, J. J.F., Witteman, J. C.M., Cao, X., de Craen, A. J.M., Bakker, S. J.L., Psaty, B. M., Starr, J. M., Hofman, A., Wouter Jukema, J., Deary, I. J., Hayward, C., van der Harst, P., Lowe, G. D.O., Folsom, A. R., Strachan, D. P., Smith, N., de Maat, M. P.M., and O'Donnell, C.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Journal Name:European Journal of Human Genetics
Publisher:Nature Publishing Group
ISSN:1018-4813
ISSN (Online):1476-5438
Published Online:21 October 2015

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