Genomic regulation of VWF levels in health and disease

Washington University, Saint Louis MO

Investigators

Abstract

PROJECT SUMMARY: Project 1 Von Willebrand Factor levels are a complex trait with an estimated heritability of 30-50%, and represent a risk factor for bleeding, thrombosis and cardiovascular disease. Genetic studies of VWF antigen levels (VWF:Ag) have been successful in identifying more than two dozen loci associated with levels but have fallen short of identifying the genes driving the associations or elucidating the underlying biological mechanisms of the associated genes. VWF levels have been shown to be 25% higher in individuals of African Ancestry, who are at increased risk of cardiovascular disease, and the mechanisms that account for this difference are not understood. Approximately 35% of patients with low VWF (30-50 IU/dL) do not have a pathogenic variant in VWF. Project 1 will focus on resolving, by identifying common and rare variants, including complex loci, the condition called low von Willebrand factor; the 20-25% increase in VWF levels seen in individuals from African Ancestry; and the increase in VWF levels observed with aging. Cohorts of subjects with low VWF, with no sequence variants in VWF will undergo whole genome and long read sequencing. Whole genome sequencing of multiple multiethnic cohorts will allow for admixture studies that will leverage the power of trans-ethnic fine mapping and haplotype association. We have recently performed whole genome sequencing (WGS) of a cohort of patients with low VWF and no mutations in VWF (n=339). In Aim 1 We will perform whole genome sequencing of a joint discovery French cohort with Low VWF and no mutations in VWF (n=300) as well as the Genes and Blood Clotting Study (n=1189). We will use available databases such as dbGaP and UK Biobank, collaborate with the CHARGE Hemostasis Working Group for replication of identified variants in the cohort of individuals with low VWF. With these discoveries (and the multiomics approach of Project 2) we will generate polygenic risk scores for low VWF and VWD. In Aim 2a we will perform WGS in available cohorts of individuals of multiethnic ancestry, intentionally selected to enrich for novel associations, as they include: participants from non-European ancestries and extensive admixture, that we will leverage in trans-ethnic fine mapping and haplotype association. We will also incorporate local ancestry in association testing to identify alleles with differential effects based on local ancestry this will be performed for all admixed populations. As in SA1 we will collaborate with the CHARGE Hemostasis Working Group for replication of identified variants. Finally, in Aim 2b, and in order to characterize multiple complex genetic loci associated with VWF levels in a multi ethnic cohort, we will use long read sequencing technology developed at the Washington University McDonnell Genome Institute to generate complex genomic maps of 120 African American, 100 European American, 100 Hispanic Americans and 100 Asian Americans and perform association studies with VWF levels and other complex traits involved in VWD and VWF biology. Taken together, these analyses will provide the first large-scale, well- powered, systematic investigation of the contribution of complex variants to human VWF and VWD.