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

Janine Loon, Abbas Dehghan, WH Tang, S Trompet, WL McArdle, FW Asselbergs, MH Chen, LM Lopez, JE Huffman, Frank Leebeek, S Basu, DJ Stott, A Rumley, RT Gansevoort, G Davies, JJF Wilson, JCM Witteman, XT Cao, AJM de Craen, SJL BakkerBM Psaty, JM Starr, Bert Hofman, JW Jukema, IJ Deary, C Hayward, P van der Harst, GDO Lowe, AR Folsom, DP Strachan, N Smith, Moniek de Maat, C O'Donnell

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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 x 10(-8) and comprised five loci on four different chromosomes: 6q24 (smallest P-value 5.8 x 10(-10)), 9q34 (2.4 x 10(-64)), 12p13 (5.3x 10(-22)), 12q23 (1.2 x 10(-8)) and 13q13 (2.6 x 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.
Original languageUndefined/Unknown
Pages (from-to)1035-1040
Number of pages6
JournalEuropean Journal of Human Genetics
Volume24
Issue number7
DOIs
Publication statusPublished - 2016

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