Regions on Chromosomes 1 and 14 Are Associated with VWF:Ag Levels in African Americans Using Mapping By Admixture Linkage Disequilibrium

Background: VWF:Ag is highly heritable, however, despite genome-wide linkage and association analysis, mostly in European derived populations, the genetic basis for VWF levels is only partially understood. African Americans (AfAm) have significantly higher VWF:Ag than European Americans: although variants in VWF and ABO can account for some of this, it is not clear whether they explain all of this ethnic difference. A powerful method to identify chromosomal regions that account for ethnic differences is mapping by admixture linkage disequilibrium (MALD). MALD uses markers that differ markedly in allele frequency between ancestral populations, estimates the global ancestry for each individual, and compares local ancestry between subjects with different trait values to global estimates to identify regions of the genome that account for the ethnic differences of a trait.

Hypothesis: Loci that are associated with VWF:Ag levels in AfAm can be mapped using MALD.

Methods: From 188 AfAm healthy volunteers from the Zimmerman Program for the Molecular and Clinical Biology of VWD, 96 were selected to have 98≤VWF:Ag≥ 164 IU which represent the <25% and >75% of VWF:Ag distribution. They were genotyped using Illumina HumanCoreExome genome-wide SNP chip. SNPs were selected for MALD if they had allele frequency difference between ancestral population (YRI and CEU from HapMap) of >0.4. Related and non-admixed individuals were excluded. Extreme trait analysis was performed using ADMIXMAP.

Results: 16 males and 68 females (mean age 41 years, SD=13) of whom 41 had with Ag≤98and 43 with Ag ≥164 IU were subjected to analysis with 2254 ancestry informative markers across the genome with a mean spacing of 1.8 cM (1.3 Mb). Estimated African ancestry was 79% (SD=13%, range 24-96%), while European ancestry was 20% (SD=12%, range 4-72%). Comparing the subjects at extremes of VWF, regions on chrs 1 (110-147 Mb) and 14 (22-40 Mb) had |Z| scores >3 (p<0.0025) which is the conventional cut-off in MALD studies. At chrs 1 and 14, greater African admixture was associated with higher VWF:Ag, consistent with the expected direction. No significant admixture signal was observed at the VWF (p=0.39) or ABO (p=0.48) loci, which may represent low power due to small sample size.

Discussion: These pilot results require replication in a larger number of independent subjects, as well as fine-mapping to identify the underlying variants responsible for differences in VWF between individuals.