Genome-wide association studies identify genetic loci for low von Willebrand factor levels.
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.
Department of Hematology, Erasmus University Medical Centre, Rotterdam, The Netherlands.
Janine
J
van Loon
Department of Epidemiology, Erasmus University Medical Centre, Rotterdam, The Netherlands.
Abbas
A
Dehghan
Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA.
Tang
T
Weihong
Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
Stella
S
Trompet
School of Social and Community Medicine, University of Bristol, Bristol, UK.
Wendy L
WL
McArdle
Department of Cardiology, Heart Long Institute, University Medical Centre Utrecht, Utrecht, The Netherlands.|Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, The Netherlands.
Folkert  W
FW
Asselbergs
Cardiovascular Health Research Unit, Department of Medicine, Epidemiology and Health Services, University of Washington, Seattle, WA, USA.
Ming-Huei
MH
Chen
Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, UK.|Department of Psychology, The University of Edinburgh, Edinburgh, UK.
Lorna M
LM
Lopez
MRC IGMM, University of Edinburgh, Edinburgh, UK.
Jennifer E
JE
Huffman
Department of Hematology, Erasmus University Medical Centre, Rotterdam, The Netherlands.
Frank W G
FW
Leebeek
Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA.
Saonli
S
Basu
Institute of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow, Glasgow, UK.
David J
DJ
Stott
Division of Cardiovascular and Medical Sciences, University of Glasgow, Royal Infirmary, Glasgow, UK.
Ann
A
Rumley
Department of Internal Medicine, University Medical Center Groningen, Groningen, The Netherlands.
Ron T
RT
Gansevoort
Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, UK.|Geriatric Medicine Unit, The University of Edinburgh, Western General Hospital, Edinburgh, UK.
Gail
G
Davies
MRC IGMM, University of Edinburgh, Edinburgh, UK.
James J F
JJ
Wilson
Department of Epidemiology, Erasmus University Medical Centre, Rotterdam, The Netherlands.
Jacqueline C M
JC
Witteman
Divisions of Biostatistics, University of Minnesota, Minneapolis, MN, USA.
Xiting
X
Cao
Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
Anton J M
AJ
de Craen
Department of Internal Medicine, University Medical Center Groningen, Groningen, The Netherlands.
Stephan J L
SJ
Bakker
Cardiovascular Health Research Unit, Department of Medicine, Epidemiology and Health Services, University of Washington, Seattle, WA, USA.
Bruce M
BM
Psaty
Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, UK.|Department of Psychology, The University of Edinburgh, Edinburgh, UK.
John M
JM
Starr
Department of Epidemiology, Erasmus University Medical Centre, Rotterdam, The Netherlands.
Albert
A
Hofman
Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
J
J
Wouter Jukema
Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, UK.|Geriatric Medicine Unit, The University of Edinburgh, Western General Hospital, Edinburgh, UK.
Ian J
IJ
Deary
MRC IGMM, University of Edinburgh, Edinburgh, UK.
Caroline
C
Hayward
Department of Internal Medicine, University Medical Center Groningen, Groningen, The Netherlands.
Pim
P
van der Harst
Institute of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow, Glasgow, UK.
Gordon D O
GD
Lowe
Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA.
Aaron R
AR
Folsom
Division of Cardiovascular and Medical Sciences, University of Glasgow, Royal Infirmary, Glasgow, UK.
David P
DP
Strachan
Department of Epidemiology, University of Washington, Seattle, WA, USA.|Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development, Seattle, WA, USA.|Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA.
Nicolas
N
Smith
Department of Hematology, Erasmus University Medical Centre, Rotterdam, The Netherlands.
Moniek P M
MP
de Maat
Cardiovascular Health Research Unit, Department of Medicine, Epidemiology and Health Services, University of Washington, Seattle, WA, USA.
Christopher
C
O'Donnell
D000017:ABO Blood-Group System / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*; D050683:R-SNARE Proteins / Q000235:genetics; D044465:White People / Q000235:genetics; D014842:von Willebrand Diseases / Q000097:blood / Q000235:genetics*; D014841:von Willebrand Factor / Q000235:genetics / Q000378:metabolism*
D000017:ABO Blood-Group System; D009419:Nerve Tissue Proteins; D011506:Proteins; D050683:R-SNARE Proteins; C484767:STXBP5 protein, human; C502094:UFM1 protein, human; C029417:Von Willebrand antigen; D014841:von Willebrand Factor