Coagulation factor VII (FVII) and factor VIII (FVIII), and its carrier protein von Willebrand factor (vWF) are implicated in in modulating the risk of arterial and venous thrombosis. This study brings together extensive whole genome sequence (WGS) resources, hemostasis phenotypes, and capitalizes on advances in computational analysis in order to better understand the genetic architecture of hemostatic factors.
We leveraged Freeze 6 WGS from the NIH NHLBI Trans-Omics for Precision Medicine (TOPMed) program. Plasma levels of FVII (n= 16,335), FVIII (n= 19,766), and vWF (n= 14,020) were harmonized across 9 studies that included participants of European, African, Asian, and Hispanic ancestry. Association analyses were conducted across all individuals using inverse normalized and rescaled residuals adjusting for age, sex, ancestry, principal components, and a kinship matrix. Analyses were conducted on the Analysis Commons cloud computing platform using the SMMAT function implemented in GENESIS. Single-variant analyses assessed all variants with a minor allele count ≥40. Aggregate analyses grouped low-frequency and rare variants (MAF<0.05) by gene, using 3 strategies for selection of variants within gene-based aggregation units: 1) loss of function (LOF) variants, 2) LOF and deleterious missense variants, and 3) coding, enhancer and promoter variants.
Single-variant analyses identified significant associations (P<5E-8) at 4 known loci for FVII, 8 for FVIII, and 8 for vWF. Three new associations included rs538727675 located between FNDC3B and GHSR associated with FVIII (MAF=0.0015; P=2.2E-8), rs114894279 downstream of TBL1XR1 associated with FVIII (MAF=0.012; P=3.4E-8), and rs147142418 in DPF3 associated with vWF (MAF=0.017; P=1.1E-8). Conditional analyses revealed multiple independent signals at the F7, VWF, STAB2, and ABO loci. Gene-based aggregate analyses identified associations at 1 known locus for FVII (F7), and 3 known loci each for vWF and FVIII (VWF, STAB2, and ABO). Additionally, LOF variants in CD36 were associated with FVIII, representing a novel locus for FVIII. The driving variant, rs3211938, causes CD36 deficiency and is associated with a range of hematological phenotypes.
WGS analysis of hemostatic factors yielded novel genetic associations with FVIII and vWF. Replication of these findings will be completed in up to 30,000 individuals from studies with imputed genotypes based on TOPMed as a reference panel.