title: Linkage analysis identifies a locus for plasma von Willebrand factor undetected by genome-wide association.
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.
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Karl C
authors.initials: KC
authors.lastname: Desch
authors.forename: Ayse B
authors.initials: AB
authors.lastname: Ozel
authors.forename: David
authors.initials: D
authors.lastname: Siemieniak
authors.forename: Yossi
authors.initials: Y
authors.lastname: Kalish
authors.forename: Jordan A
authors.initials: JA
authors.lastname: Shavit
authors.forename: Courtney D
authors.initials: CD
authors.lastname: Thornburg
authors.forename: Anjali A
authors.initials: AA
authors.lastname: Sharathkumar
authors.forename: Caitlin P
authors.initials: CP
authors.lastname: McHugh
authors.forename: Cathy C
authors.initials: CC
authors.lastname: Laurie
authors.forename: Andrew
authors.initials: A
authors.lastname: Crenshaw
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Mirel
authors.forename: Yoonhee
authors.initials: Y
authors.lastname: Kim
authors.forename: Cheryl D
authors.initials: CD
authors.lastname: Cropp
authors.forename: Anne M
authors.initials: AM
authors.lastname: Molloy
authors.forename: Peadar N
authors.initials: PN
authors.lastname: Kirke
authors.forename: Joan E
authors.initials: JE
authors.lastname: Bailey-Wilson
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Wilson
authors.forename: James L
authors.initials: JL
authors.lastname: Mills
authors.forename: John M
authors.initials: JM
authors.lastname: Scott
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Brody
authors.forename: Jun Z
authors.initials: JZ
authors.lastname: Li
authors.forename: David
authors.initials: D
authors.lastname: Ginsburg
mesh_terms: D000017:ABO Blood-Group System / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics*; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D019295:Computational Biology; D005787:Gene Frequency; D008040:Genetic Linkage / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008126:Lod Score; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D025341:Principal Component Analysis; D040641:Quantitative Trait Loci / Q000235:genetics*; D012737:Sex Factors; D014841:von Willebrand Factor / Q000235:genetics* / Q000378:metabolism
chemical_list: D000017:ABO Blood-Group System; D014841:von Willebrand Factor