Journal article
Linkage analysis identifies a locus for plasma von Willebrand factor undetected by genome-wide association
Proceedings of the National Academy of Sciences - PNAS, Vol.110(2), pp.588-593
01/08/2013
DOI: 10.1073/pnas.1219885110
PMCID: PMC3545809
PMID: 23267103
Abstract
The plasma glycoprotein von Willebrand factor (VWF) exhibits fivefold antigen level variation across the normal human population determined by both genetic and environmental factors. Low levels of VWF are associated with bleeding and elevated levels with increased risk for thrombosis, myocardial infarction, and stroke. To identify additional genetic determinants of VWF antigen levels and to minimize the impact of age and illness-related environmental factors, we performed genome-wide association analysis in two young and healthy cohorts (
n
= 1,152 and
n
= 2,310) and identified signals at
ABO
(
P
< 7.9E-139) and
VWF
(
P
< 5.5E-16), consistent with previous reports. Additionally, linkage analysis based on sibling structure within the cohorts, identified significant signals at chromosome 2q12–2p13 (LOD score 5.3) and at the
ABO
locus on chromosome 9q34 (LOD score 2.9) that explained 19.2% and 24.5% of the variance in VWF levels, respectively. Given its strong effect, the linkage region on chromosome 2 could harbor a potentially important determinant of bleeding and thrombosis risk. The absence of a chromosome 2 association signal in this or previous association studies suggests a causative gene harboring many genetic variants that are individually rare, but in aggregate common. These results raise the possibility that similar loci could explain a significant portion of the “missing heritability” for other complex genetic traits.
Details
- Title: Subtitle
- Linkage analysis identifies a locus for plasma von Willebrand factor undetected by genome-wide association
- Creators
- Karl C Desch - Department of Pediatrics and Communicable DiseasesAyse B Ozel - Department of Human GeneticsDavid Siemieniak - , Ann ArborYossi Kalish - , Jerusalem 91120Jordan A Shavit - Department of Pediatrics and Communicable DiseasesCourtney D Thornburg - Department of PediatricsAnjali A Sharathkumar - Department of PediatricsCaitlin P McHugh - Department of BiostatisticsCathy C Laurie - Department of BiostatisticsAndrew Crenshaw - , CambridgeDaniel B Mirel - , CambridgeYoonhee Kim - Inherited Disease Research Branch, National Human Genome Research InstituteCheryl D Cropp - Inherited Disease Research Branch, National Human Genome Research InstituteAnne M Molloy - School of Medicine andPeadar N Kirke - Child Health Epidemiology UnitJoan E Bailey-Wilson - Inherited Disease Research Branch, National Human Genome Research InstituteAlexander F Wilson - Inherited Disease Research Branch, National Human Genome Research InstituteJames L Mills - Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentJohn M Scott - School of Biochemistry and ImmunologyLawrence C Brody - Genome Technology Branch, National Human Genome Research InstituteJun Z Li - Department of Human GeneticsDavid Ginsburg - Department of Pediatrics and Communicable Diseases
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.110(2), pp.588-593
- DOI
- 10.1073/pnas.1219885110
- PMID
- 23267103
- PMCID
- PMC3545809
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Publisher
- National Academy of Sciences
- Alternative title
- VWF linkage and GWAS
- Language
- English
- Date published
- 01/08/2013
- Academic Unit
- Stead Family Department of Pediatrics; Hematology/Oncology
- Record Identifier
- 9984093210502771
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