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

Janine van Loon; Abbas Dehghan; Tang Weihong; Stella Trompet; Wendy L. McArdle; Folkert F W Asselbergs; Ming Huei Chen; Lorna M. Lopez; Jennifer E. Huffman; Frank W G Leebeek; Saonli Basu; David J. Stott; Ann Rumley; Ron T. Gansevoort; Gail Davies; James J F Wilson; Jacqueline C M Witteman; Xiting Cao; Anton J M de Craen; Stephan J L Bakker; Bruce M. Psaty; John M. Starr; Albert Hofman; J. Wouter Jukema; Ian J. Deary; Caroline Hayward; Pim van der Harst; Gordon D O Lowe; Aaron R. Folsom; David P. Strachan; Nicolas Smith; Moniek P M de Maat; Christopher O'Donnell

doi:10.1038/ejhg.2015.222

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

Janine van Loon, Abbas Dehghan, Tang Weihong, Stella Trompet, Wendy L. McArdle, Folkert F W Asselbergs, Ming Huei Chen, Lorna M. Lopez, Jennifer E. Huffman, Frank W G Leebeek, Saonli Basu, David J. Stott, Ann Rumley, Ron T. Gansevoort, Gail Davies, James J F Wilson, Jacqueline C M Witteman, Xiting Cao, Anton J M de Craen, Stephan J L BakkerBruce M. Psaty, John M. Starr, Albert Hofman, J. Wouter Jukema, Ian J. Deary, Caroline Hayward, Pim van der Harst, Gordon D O Lowe, Aaron R. Folsom, David P. Strachan, Nicolas Smith, Moniek P M de Maat, Christopher O'Donnell

Research output: Contribution to journal › Article › peer-review

37 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1035-1040
Number of pages	6
Journal	European Journal of Human Genetics
Volume	24
Issue number	7
DOIs	https://doi.org/10.1038/ejhg.2015.222
State	Published - Jul 1 2016

Bibliographical note

Funding Information:
We acknowledge the use of phenotype and genotype data from the B58C DNA collection, funded by Medical Research Council Grant G0000934 and the Wellcome Trust Grant 068545/Z/02 (http://www.b58cgene.sgul.ac.uk/).

Funding Information:
The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute Contract U01HG004402; and National Institutes of Health Contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. We acknowledge the use of phenotype and genotype data from the B58C DNA collection, funded by Medical Research Council Grant G0000934 and the Wellcome Trust Grant 068545/Z/02 (http://www.b58cgene.sgul.ac.uk/). Genotyping of the Lothian Birth Cohorts 1921 and 1936 were supported by the UK's Biotechnology and Biological Sciences Research Council (BBSRC). Phenotype collection in the Lothian Birth Cohort 1921 was supported by The Chief Scientist Office of the Scottish Government (ETM/55). Phenotype collection in the Lothian Birth Cohort 1936 was supported by Research Into Ageing (continues as part of Age UK's The Disconnected Mind project). The work was undertaken in The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (G0700704/84698). Funding from the UK's BBSRC, EPSRC, ESRC and MRC is gratefully acknowledged. PROSPER is supported by the Scottish Executive Chief Scientist Office, Health Services Research Committee grant number CZG/4/306 and the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (NGI/NOW 911-03-016). The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Scientific Research; the Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly; the Netherlands Heart Foundation (DHF-2007B159); the Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sports; the European Commission; and the Municipality of Rotterdam. Support for genotyping was provided by the Netherlands Organization for Scientific Research (NWO; 175.010.2005.011, 911.03.012) and Research Institute for Diseases in the Elderly (RIDE). This study was further supported by the Netherlands Genomics Initiative (NGI)/ NWO Project No. 050-060-810 and NWO/ZonMw Grant No. 918-76-619 and NWO/ZonMw Grant No. 918-76-619. Dr Dehghan is supported by NWO Grant (veni, 916.12.154) and the EUR Fellowship. PREVEND genetics is supported by the Dutch Kidney Foundation (Grant E033), the EU project grant GENECURE (FP-6 LSHM CT 2006 037697), the National Institutes of Health (Grant 2R01LM010098), The Netherlands Organization for Health Research and Development (NWO-Groot Grant 175.010.2007.006, NWO VENI Grant 916.761.70, ZonMw Grant 90.700.441) and the Dutch Inter-University Cardiology Institute Netherlands (ICIN). The VIS study in the Croatian island of Vis was supported through grants from the Medical Research Council UK and Ministry of Science, Education and Sport of the Republic of Croatia (No. 108-1080315-0302) and the European Union framework program 6 EUROSPAN project (Contract No. LSHGCT- 2006-018947). ORCADES was supported by the Chief Scientist Office of the Scottish Government, the Royal Society and the European Union framework program 6 EUROSPAN project (Contract No. LSHG-CT-2006- 018947). DNA extractions were performed at the Wellcome Trust Clinical Research Facility in Edinburgh.

Funding Information:
The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute Contract U01HG004402; and National Institutes of Health Contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research.

Funding Information:
1Department of Hematology, Erasmus University Medical Centre, Rotterdam, The Netherlands; 2Department of Epidemiology, Erasmus University Medical Centre, Rotterdam, The Netherlands; 3Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA; 4Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands; 5School of Social and Community Medicine, University of Bristol, Bristol, UK; 6Department of Cardiology, Heart Long Institute, University Medical Centre Utrecht, Utrecht, The Netherlands; 7Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, The Netherlands; 8Cardiovascular Health Research Unit, Department of Medicine, Epidemiology and Health Services, University of Washington, Seattle, WA, USA; 9Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, UK; 10Department of Psychology, The University of Edinburgh, Edinburgh, UK; 11MRC IGMM, University of Edinburgh, Edinburgh, UK; 12Institute of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow, Glasgow, UK; 13Division of Cardiovascular and Medical Sciences, University of Glasgow, Royal Infirmary, Glasgow, UK; 14Department of Internal Medicine, University Medical Center Groningen, Groningen, The Netherlands; 15Geriatric Medicine Unit, The University of Edinburgh, Western General Hospital, Edinburgh, UK; 16Divisions of Biostatistics, University of Minnesota, Minneapolis, MN, USA; 17Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands; 18Cardiovascular Health Research Unit, Department of Medicine, Epidemiology and Health Services, University of Washington, Seattle, WA, USA; 19Department of Epidemiology, University of Washington, Seattle, WA, USA; 20Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development, Seattle, WA, USA; 21Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA *Correspondence: Dr MPM de Maat, Department of Hematology, Erasmus University Medical Centre, Room Nb845a, PO Box 2040, Rotterdam 3000 CA, The Netherlands. Tel: +31 10 703 3442; Fax: +31 10 703 5814; E-mail: m.demaat@erasmusmc.nl Received 17 March 2014; revised 23 August 2015; accepted 11 September 2015; published online 21 October 2015

Funding Information:
PREVEND genetics is supported by the Dutch Kidney Foundation (Grant E033), the EU project grant GENECURE (FP-6 LSHM CT 2006 037697), the National Institutes of Health (Grant 2R01LM010098), The Netherlands Organization for Health Research and Development (NWO-Groot Grant 175.010.2007.006, NWO VENI Grant 916.761.70, ZonMw Grant 90.700.441) and the Dutch Inter-University Cardiology Institute Netherlands (ICIN).

Funding Information:
Genotyping of the Lothian Birth Cohorts 1921 and 1936 were supported by the UK’s Biotechnology and Biological Sciences Research Council (BBSRC). Phenotype collection in the Lothian Birth Cohort 1921 was supported by The Chief Scientist Office of the Scottish Government (ETM/55). Phenotype collection in the Lothian Birth Cohort 1936 was supported by Research Into Ageing (continues as part of Age UK’s The Disconnected Mind project). The work was undertaken in The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (G0700704/84698). Funding from the UK’s BBSRC, EPSRC, ESRC and MRC is gratefully acknowledged. PROSPER is supported by the Scottish Executive Chief Scientist Office, Health Services Research Committee grant number CZG/4/306 and the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (NGI/NOW 911-03-016). The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Scientific Research; the Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly; the Netherlands Heart Foundation (DHF-2007B159); the Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sports; the European Commission; and the Municipality of Rotterdam. Support for genotyping was provided by the Netherlands Organization for Scientific Research (NWO; 175.010.2005.011, 911.03.012) and Research Institute for Diseases in the Elderly (RIDE). This study was further supported by the Netherlands Genomics Initiative (NGI)/ NWO Project No. 050-060-810 and NWO/ZonMw Grant No. 918-76-619 and NWO/ZonMw Grant No. 918-76-619. Dr Dehghan is supported by NWO Grant (veni, 916.12.154) and the EUR Fellowship.

Funding Information:
The VIS study in the Croatian island of Vis was supported through grants from the Medical Research Council UK and Ministry of Science, Education and Sport of the Republic of Croatia (No. 108-1080315-0302) and the European Union framework program 6 EUROSPAN project (Contract No. LSHG-CT-2006-018947). ORCADES was supported by the Chief Scientist Office of the Scottish Government, the Royal Society and the European Union framework program 6 EUROSPAN project (Contract No. LSHG-CT-2006-018947). DNA extractions were performed at the Wellcome Trust Clinical Research Facility in Edinburgh.

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© 2016 Macmillan Publishers Limited. All rights reserved.

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10.1038/ejhg.2015.222

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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. J., Rumley, A., Gansevoort, R. T., Davies, G., Wilson, J. J. F., Witteman, J. C. M., Cao, X., de Craen, A. J. M., ... O'Donnell, C. (2016). Genome-wide association studies identify genetic loci for low von Willebrand factor levels. European Journal of Human Genetics, 24(7), 1035-1040. https://doi.org/10.1038/ejhg.2015.222

van Loon, J, Dehghan, A, Weihong, T, Trompet, S, McArdle, WL, Asselbergs, FFW, Chen, MH, Lopez, LM, Huffman, JE, Leebeek, FWG, Basu, S, Stott, DJ, Rumley, A, Gansevoort, RT, Davies, G, Wilson, JJF, Witteman, JCM, Cao, X, de Craen, AJM, Bakker, SJL, Psaty, BM, Starr, JM, Hofman, A, Wouter Jukema, J, Deary, IJ, Hayward, C, van der Harst, P, Lowe, GDO, Folsom, AR, Strachan, DP, Smith, N, de Maat, MPM & O'Donnell, C 2016, 'Genome-wide association studies identify genetic loci for low von Willebrand factor levels', European Journal of Human Genetics, vol. 24, no. 7, pp. 1035-1040. https://doi.org/10.1038/ejhg.2015.222

@article{515b433b5f3747ebb4ed37c0539c30c2,

title = "Genome-wide association studies identify genetic loci for low von Willebrand factor levels",

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.",

author = "{van Loon}, Janine and Abbas Dehghan and Tang Weihong and Stella Trompet and McArdle, {Wendy L.} and Asselbergs, {Folkert F W} and Chen, {Ming Huei} and Lopez, {Lorna M.} and Huffman, {Jennifer E.} and Leebeek, {Frank W G} and Saonli Basu and Stott, {David J.} and Ann Rumley and Gansevoort, {Ron T.} and Gail Davies and Wilson, {James J F} and Witteman, {Jacqueline C M} and Xiting Cao and {de Craen}, {Anton J M} and Bakker, {Stephan J L} and Psaty, {Bruce M.} and Starr, {John M.} and Albert Hofman and {Wouter Jukema}, J. and Deary, {Ian J.} and Caroline Hayward and {van der Harst}, Pim and Lowe, {Gordon D O} and Folsom, {Aaron R.} and Strachan, {David P.} and Nicolas Smith and {de Maat}, {Moniek P M} and Christopher O'Donnell",

note = "Funding Information: We acknowledge the use of phenotype and genotype data from the B58C DNA collection, funded by Medical Research Council Grant G0000934 and the Wellcome Trust Grant 068545/Z/02 (http://www.b58cgene.sgul.ac.uk/). Funding Information: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute Contract U01HG004402; and National Institutes of Health Contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. We acknowledge the use of phenotype and genotype data from the B58C DNA collection, funded by Medical Research Council Grant G0000934 and the Wellcome Trust Grant 068545/Z/02 (http://www.b58cgene.sgul.ac.uk/). Genotyping of the Lothian Birth Cohorts 1921 and 1936 were supported by the UK's Biotechnology and Biological Sciences Research Council (BBSRC). Phenotype collection in the Lothian Birth Cohort 1921 was supported by The Chief Scientist Office of the Scottish Government (ETM/55). Phenotype collection in the Lothian Birth Cohort 1936 was supported by Research Into Ageing (continues as part of Age UK's The Disconnected Mind project). The work was undertaken in The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (G0700704/84698). Funding from the UK's BBSRC, EPSRC, ESRC and MRC is gratefully acknowledged. PROSPER is supported by the Scottish Executive Chief Scientist Office, Health Services Research Committee grant number CZG/4/306 and the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (NGI/NOW 911-03-016). The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Scientific Research; the Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly; the Netherlands Heart Foundation (DHF-2007B159); the Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sports; the European Commission; and the Municipality of Rotterdam. Support for genotyping was provided by the Netherlands Organization for Scientific Research (NWO; 175.010.2005.011, 911.03.012) and Research Institute for Diseases in the Elderly (RIDE). This study was further supported by the Netherlands Genomics Initiative (NGI)/ NWO Project No. 050-060-810 and NWO/ZonMw Grant No. 918-76-619 and NWO/ZonMw Grant No. 918-76-619. Dr Dehghan is supported by NWO Grant (veni, 916.12.154) and the EUR Fellowship. PREVEND genetics is supported by the Dutch Kidney Foundation (Grant E033), the EU project grant GENECURE (FP-6 LSHM CT 2006 037697), the National Institutes of Health (Grant 2R01LM010098), The Netherlands Organization for Health Research and Development (NWO-Groot Grant 175.010.2007.006, NWO VENI Grant 916.761.70, ZonMw Grant 90.700.441) and the Dutch Inter-University Cardiology Institute Netherlands (ICIN). The VIS study in the Croatian island of Vis was supported through grants from the Medical Research Council UK and Ministry of Science, Education and Sport of the Republic of Croatia (No. 108-1080315-0302) and the European Union framework program 6 EUROSPAN project (Contract No. LSHGCT- 2006-018947). ORCADES was supported by the Chief Scientist Office of the Scottish Government, the Royal Society and the European Union framework program 6 EUROSPAN project (Contract No. LSHG-CT-2006- 018947). DNA extractions were performed at the Wellcome Trust Clinical Research Facility in Edinburgh. Funding Information: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute Contract U01HG004402; and National Institutes of Health Contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. Funding Information: 1Department of Hematology, Erasmus University Medical Centre, Rotterdam, The Netherlands; 2Department of Epidemiology, Erasmus University Medical Centre, Rotterdam, The Netherlands; 3Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA; 4Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands; 5School of Social and Community Medicine, University of Bristol, Bristol, UK; 6Department of Cardiology, Heart Long Institute, University Medical Centre Utrecht, Utrecht, The Netherlands; 7Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, The Netherlands; 8Cardiovascular Health Research Unit, Department of Medicine, Epidemiology and Health Services, University of Washington, Seattle, WA, USA; 9Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, UK; 10Department of Psychology, The University of Edinburgh, Edinburgh, UK; 11MRC IGMM, University of Edinburgh, Edinburgh, UK; 12Institute of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow, Glasgow, UK; 13Division of Cardiovascular and Medical Sciences, University of Glasgow, Royal Infirmary, Glasgow, UK; 14Department of Internal Medicine, University Medical Center Groningen, Groningen, The Netherlands; 15Geriatric Medicine Unit, The University of Edinburgh, Western General Hospital, Edinburgh, UK; 16Divisions of Biostatistics, University of Minnesota, Minneapolis, MN, USA; 17Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands; 18Cardiovascular Health Research Unit, Department of Medicine, Epidemiology and Health Services, University of Washington, Seattle, WA, USA; 19Department of Epidemiology, University of Washington, Seattle, WA, USA; 20Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development, Seattle, WA, USA; 21Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA *Correspondence: Dr MPM de Maat, Department of Hematology, Erasmus University Medical Centre, Room Nb845a, PO Box 2040, Rotterdam 3000 CA, The Netherlands. Tel: +31 10 703 3442; Fax: +31 10 703 5814; E-mail: m.demaat@erasmusmc.nl Received 17 March 2014; revised 23 August 2015; accepted 11 September 2015; published online 21 October 2015 Funding Information: PREVEND genetics is supported by the Dutch Kidney Foundation (Grant E033), the EU project grant GENECURE (FP-6 LSHM CT 2006 037697), the National Institutes of Health (Grant 2R01LM010098), The Netherlands Organization for Health Research and Development (NWO-Groot Grant 175.010.2007.006, NWO VENI Grant 916.761.70, ZonMw Grant 90.700.441) and the Dutch Inter-University Cardiology Institute Netherlands (ICIN). Funding Information: Genotyping of the Lothian Birth Cohorts 1921 and 1936 were supported by the UK{\textquoteright}s Biotechnology and Biological Sciences Research Council (BBSRC). Phenotype collection in the Lothian Birth Cohort 1921 was supported by The Chief Scientist Office of the Scottish Government (ETM/55). Phenotype collection in the Lothian Birth Cohort 1936 was supported by Research Into Ageing (continues as part of Age UK{\textquoteright}s The Disconnected Mind project). The work was undertaken in The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (G0700704/84698). Funding from the UK{\textquoteright}s BBSRC, EPSRC, ESRC and MRC is gratefully acknowledged. PROSPER is supported by the Scottish Executive Chief Scientist Office, Health Services Research Committee grant number CZG/4/306 and the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (NGI/NOW 911-03-016). The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Scientific Research; the Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly; the Netherlands Heart Foundation (DHF-2007B159); the Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sports; the European Commission; and the Municipality of Rotterdam. Support for genotyping was provided by the Netherlands Organization for Scientific Research (NWO; 175.010.2005.011, 911.03.012) and Research Institute for Diseases in the Elderly (RIDE). This study was further supported by the Netherlands Genomics Initiative (NGI)/ NWO Project No. 050-060-810 and NWO/ZonMw Grant No. 918-76-619 and NWO/ZonMw Grant No. 918-76-619. Dr Dehghan is supported by NWO Grant (veni, 916.12.154) and the EUR Fellowship. Funding Information: The VIS study in the Croatian island of Vis was supported through grants from the Medical Research Council UK and Ministry of Science, Education and Sport of the Republic of Croatia (No. 108-1080315-0302) and the European Union framework program 6 EUROSPAN project (Contract No. LSHG-CT-2006-018947). ORCADES was supported by the Chief Scientist Office of the Scottish Government, the Royal Society and the European Union framework program 6 EUROSPAN project (Contract No. LSHG-CT-2006-018947). DNA extractions were performed at the Wellcome Trust Clinical Research Facility in Edinburgh. Publisher Copyright: {\textcopyright} 2016 Macmillan Publishers Limited. All rights reserved.",

year = "2016",

month = jul,

day = "1",

doi = "10.1038/ejhg.2015.222",

language = "English (US)",

volume = "24",

pages = "1035--1040",

journal = "European Journal of Human Genetics",

issn = "1018-4813",

publisher = "Nature Publishing Group",

number = "7",

}

TY - JOUR

T1 - Genome-wide association studies identify genetic loci for low von Willebrand factor levels

AU - van Loon, Janine

AU - Dehghan, Abbas

AU - Weihong, Tang

AU - Trompet, Stella

AU - McArdle, Wendy L.

AU - Asselbergs, Folkert F W

AU - Chen, Ming Huei

AU - Lopez, Lorna M.

AU - Huffman, Jennifer E.

AU - Leebeek, Frank W G

AU - Basu, Saonli

AU - Stott, David J.

AU - Rumley, Ann

AU - Gansevoort, Ron T.

AU - Davies, Gail

AU - Wilson, James J F

AU - Witteman, Jacqueline C M

AU - Cao, Xiting

AU - de Craen, Anton J M

AU - Bakker, Stephan J L

AU - Psaty, Bruce M.

AU - Starr, John M.

AU - Hofman, Albert

AU - Wouter Jukema, J.

AU - Deary, Ian J.

AU - Hayward, Caroline

AU - van der Harst, Pim

AU - Lowe, Gordon D O

AU - Folsom, Aaron R.

AU - Strachan, David P.

AU - Smith, Nicolas

AU - de Maat, Moniek P M

AU - O'Donnell, Christopher

N1 - Funding Information: We acknowledge the use of phenotype and genotype data from the B58C DNA collection, funded by Medical Research Council Grant G0000934 and the Wellcome Trust Grant 068545/Z/02 (http://www.b58cgene.sgul.ac.uk/). Funding Information: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute Contract U01HG004402; and National Institutes of Health Contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. We acknowledge the use of phenotype and genotype data from the B58C DNA collection, funded by Medical Research Council Grant G0000934 and the Wellcome Trust Grant 068545/Z/02 (http://www.b58cgene.sgul.ac.uk/). Genotyping of the Lothian Birth Cohorts 1921 and 1936 were supported by the UK's Biotechnology and Biological Sciences Research Council (BBSRC). Phenotype collection in the Lothian Birth Cohort 1921 was supported by The Chief Scientist Office of the Scottish Government (ETM/55). Phenotype collection in the Lothian Birth Cohort 1936 was supported by Research Into Ageing (continues as part of Age UK's The Disconnected Mind project). The work was undertaken in The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (G0700704/84698). Funding from the UK's BBSRC, EPSRC, ESRC and MRC is gratefully acknowledged. PROSPER is supported by the Scottish Executive Chief Scientist Office, Health Services Research Committee grant number CZG/4/306 and the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (NGI/NOW 911-03-016). The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Scientific Research; the Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly; the Netherlands Heart Foundation (DHF-2007B159); the Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sports; the European Commission; and the Municipality of Rotterdam. Support for genotyping was provided by the Netherlands Organization for Scientific Research (NWO; 175.010.2005.011, 911.03.012) and Research Institute for Diseases in the Elderly (RIDE). This study was further supported by the Netherlands Genomics Initiative (NGI)/ NWO Project No. 050-060-810 and NWO/ZonMw Grant No. 918-76-619 and NWO/ZonMw Grant No. 918-76-619. Dr Dehghan is supported by NWO Grant (veni, 916.12.154) and the EUR Fellowship. PREVEND genetics is supported by the Dutch Kidney Foundation (Grant E033), the EU project grant GENECURE (FP-6 LSHM CT 2006 037697), the National Institutes of Health (Grant 2R01LM010098), The Netherlands Organization for Health Research and Development (NWO-Groot Grant 175.010.2007.006, NWO VENI Grant 916.761.70, ZonMw Grant 90.700.441) and the Dutch Inter-University Cardiology Institute Netherlands (ICIN). The VIS study in the Croatian island of Vis was supported through grants from the Medical Research Council UK and Ministry of Science, Education and Sport of the Republic of Croatia (No. 108-1080315-0302) and the European Union framework program 6 EUROSPAN project (Contract No. LSHGCT- 2006-018947). ORCADES was supported by the Chief Scientist Office of the Scottish Government, the Royal Society and the European Union framework program 6 EUROSPAN project (Contract No. LSHG-CT-2006- 018947). DNA extractions were performed at the Wellcome Trust Clinical Research Facility in Edinburgh. Funding Information: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute Contract U01HG004402; and National Institutes of Health Contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. Funding Information: 1Department of Hematology, Erasmus University Medical Centre, Rotterdam, The Netherlands; 2Department of Epidemiology, Erasmus University Medical Centre, Rotterdam, The Netherlands; 3Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA; 4Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands; 5School of Social and Community Medicine, University of Bristol, Bristol, UK; 6Department of Cardiology, Heart Long Institute, University Medical Centre Utrecht, Utrecht, The Netherlands; 7Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, The Netherlands; 8Cardiovascular Health Research Unit, Department of Medicine, Epidemiology and Health Services, University of Washington, Seattle, WA, USA; 9Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, UK; 10Department of Psychology, The University of Edinburgh, Edinburgh, UK; 11MRC IGMM, University of Edinburgh, Edinburgh, UK; 12Institute of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow, Glasgow, UK; 13Division of Cardiovascular and Medical Sciences, University of Glasgow, Royal Infirmary, Glasgow, UK; 14Department of Internal Medicine, University Medical Center Groningen, Groningen, The Netherlands; 15Geriatric Medicine Unit, The University of Edinburgh, Western General Hospital, Edinburgh, UK; 16Divisions of Biostatistics, University of Minnesota, Minneapolis, MN, USA; 17Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands; 18Cardiovascular Health Research Unit, Department of Medicine, Epidemiology and Health Services, University of Washington, Seattle, WA, USA; 19Department of Epidemiology, University of Washington, Seattle, WA, USA; 20Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development, Seattle, WA, USA; 21Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA *Correspondence: Dr MPM de Maat, Department of Hematology, Erasmus University Medical Centre, Room Nb845a, PO Box 2040, Rotterdam 3000 CA, The Netherlands. Tel: +31 10 703 3442; Fax: +31 10 703 5814; E-mail: m.demaat@erasmusmc.nl Received 17 March 2014; revised 23 August 2015; accepted 11 September 2015; published online 21 October 2015 Funding Information: PREVEND genetics is supported by the Dutch Kidney Foundation (Grant E033), the EU project grant GENECURE (FP-6 LSHM CT 2006 037697), the National Institutes of Health (Grant 2R01LM010098), The Netherlands Organization for Health Research and Development (NWO-Groot Grant 175.010.2007.006, NWO VENI Grant 916.761.70, ZonMw Grant 90.700.441) and the Dutch Inter-University Cardiology Institute Netherlands (ICIN). Funding Information: Genotyping of the Lothian Birth Cohorts 1921 and 1936 were supported by the UK’s Biotechnology and Biological Sciences Research Council (BBSRC). Phenotype collection in the Lothian Birth Cohort 1921 was supported by The Chief Scientist Office of the Scottish Government (ETM/55). Phenotype collection in the Lothian Birth Cohort 1936 was supported by Research Into Ageing (continues as part of Age UK’s The Disconnected Mind project). The work was undertaken in The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (G0700704/84698). Funding from the UK’s BBSRC, EPSRC, ESRC and MRC is gratefully acknowledged. PROSPER is supported by the Scottish Executive Chief Scientist Office, Health Services Research Committee grant number CZG/4/306 and the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (NGI/NOW 911-03-016). The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Scientific Research; the Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly; the Netherlands Heart Foundation (DHF-2007B159); the Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sports; the European Commission; and the Municipality of Rotterdam. Support for genotyping was provided by the Netherlands Organization for Scientific Research (NWO; 175.010.2005.011, 911.03.012) and Research Institute for Diseases in the Elderly (RIDE). This study was further supported by the Netherlands Genomics Initiative (NGI)/ NWO Project No. 050-060-810 and NWO/ZonMw Grant No. 918-76-619 and NWO/ZonMw Grant No. 918-76-619. Dr Dehghan is supported by NWO Grant (veni, 916.12.154) and the EUR Fellowship. Funding Information: The VIS study in the Croatian island of Vis was supported through grants from the Medical Research Council UK and Ministry of Science, Education and Sport of the Republic of Croatia (No. 108-1080315-0302) and the European Union framework program 6 EUROSPAN project (Contract No. LSHG-CT-2006-018947). ORCADES was supported by the Chief Scientist Office of the Scottish Government, the Royal Society and the European Union framework program 6 EUROSPAN project (Contract No. LSHG-CT-2006-018947). DNA extractions were performed at the Wellcome Trust Clinical Research Facility in Edinburgh. Publisher Copyright: © 2016 Macmillan Publishers Limited. All rights reserved.

PY - 2016/7/1

Y1 - 2016/7/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84944936745&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84944936745&partnerID=8YFLogxK

U2 - 10.1038/ejhg.2015.222

DO - 10.1038/ejhg.2015.222

M3 - Article

C2 - 26486471

AN - SCOPUS:84944936745

SN - 1018-4813

VL - 24

SP - 1035

EP - 1040

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

IS - 7

ER -

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

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