Linkage analysis identifies a locus for plasma von Willebrand factor undetected by genome-wide association

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.

• Publication year

  2012

• Venue

  Proceedings of the National Academy of Sciences of the United States of America

• Publication date

  2012-12-24

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1073/pnas.1219885110PMID 23267103PMCID PMC3545809
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• The lack of a chromosome 2 association signal in this and prior association studies is consistent with a causative gene carrying many individually rare variants that are common in aggregate.

  Confidence 0.86

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewKiller Whale (322360f1c1) review
• The chromosome 2 linkage region could contain an important determinant of bleeding and thrombosis risk.

  Confidence 0.88

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewKiller Whale (322360f1c1) review
• Linkage analysis identified a significant signal at chromosome 2q12-2p13 and a second signal at the ABO locus, explaining 19.2% and 24.5% of the variance in plasma von Willebrand factor levels, respectively.

  Confidence 0.97

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewKiller Whale (322360f1c1) review
• Genome-wide association analysis in two young, healthy cohorts identified signals at the ABO and VWF loci for plasma von Willebrand factor antigen levels.

  Confidence 0.98

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewKiller Whale (322360f1c1) review

• abo locus

  genetic locus, gene region

  The genomic region containing ABO, the blood-group gene on chromosome 9q34.

  Aliases: ABO

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewKiller Whale (322360f1c1) review
• association studies

  study type

  Genetic studies that test statistical association between variants and a trait across the genome or at specific loci.

  Aliases: association study, association analyses

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewKiller Whale (322360f1c1) review
• bleeding and thrombosis risk

  clinical outcome

  The clinical risk of abnormal bleeding or blood clot formation associated with altered hemostasis.

  Aliases: bleeding risk, thrombosis risk

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewKiller Whale (322360f1c1) review
• chromosome 2q12-2p13

  chromosomal region, genetic locus

  A chromosomal region on human chromosome 2 highlighted by linkage evidence in this study.

  Aliases: 2q12-2p13, chromosome 2 linkage region

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewKiller Whale (322360f1c1) review
• genome-wide association analysis

  method

  A genome-wide scan that tests common genetic variants for association with a measured trait.

  Aliases: GWAS

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewKiller Whale (322360f1c1) review
• linkage analysis

  method

  A family-based genetic mapping approach that searches for chromosomal regions shared with a trait within relatives.

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewKiller Whale (322360f1c1) review
• plasma von willebrand factor antigen levels

  trait, biomarker

  The circulating amount of von Willebrand factor antigen measured in plasma as a quantitative trait.

  Aliases: VWF antigen levels, VWF levels

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewKiller Whale (322360f1c1) review
• rare variants

  genetic variant class

  Genetic variants that occur at low frequency in the population, often individually hard to detect in association testing.

  Aliases: individually rare variants

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewKiller Whale (322360f1c1) review
• vwf locus

  genetic locus, gene region

  The genomic region containing the VWF gene, which encodes von Willebrand factor.

  Aliases: VWF

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewKiller Whale (322360f1c1) review

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