Journal Article

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

Mirel, Daniel B., Wilson, Alexander F., McHugh, Caitlin P., Cropp, Cheryl D., Ginsburg, David, Siemieniak, David, Li, Jun Z., Crenshaw, Andrew, Thornburg, Courtney D., Shavit, Jordan A., Molloy, Anne M., Scott, John M., Kirke, Peadar N., Ozel, Ayse B., Sharathkumar, Anjali A., Brody, Lawrence C., Desch, Karl C., Mills, James L., Kalish, Yossi, Kim, Yoonhee, Laurie, Cathy C., Bailey-Wilson, Joan E.

2013

Overview

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.

• Publisher: National Academy of Sciences
• Subject: ABO Blood-Group System - genetics / Adolescent / Adult / Age Factors / Alleles / Antigens / Biological Sciences / blood coagulation factors / Blood grouping / Blood plasma / Chromosomes / Chromosomes, Human, Pair 2 - genetics / Chromosomes, Human, Pair 9 - genetics / Computational Biology / Environmental factors / Gene Frequency / Gene loci / genes / Genetic Linkage - genetics / Genetic loci / genetic traits / Genetic variance / genetic variation / Genetics / Genome-Wide Association Study / Genomics / Genotype / Glycoproteins / Haplotypes / Haplotypes - genetics / hemorrhage / heritability / Human genetics / human population / Human populations / Humans / loci / Lod Score / Medical genetics / Myocardial infarction / P values / Plasma / Polymorphism, Single Nucleotide - genetics / Principal Component Analysis / Quantitative Trait Loci - genetics / risk / Sex Factors / stroke / Thromboembolism / thrombosis / variance / von Willebrand Factor - genetics / von Willebrand Factor - metabolism