Background: Coagulation factor VIII (FVIII) and its carrier protein von Willebrand factor (vWF) are implicated in increasing the risk of thrombotic events.

Aims: We aimed to combine whole genome sequencing data from NHLBI’s TOPMed program with TOPMed-based imputation of genotypes in the CHARGE consortium to identify genetic associations with plasma levels of FVIII and vWF.

Methods: We included 9 TOPMed studies with European, African, Asian, and Hispanic ancestry participants. Association analyses in TOPMed were conducted across all individuals adjusting for age, sex, ancestry, principal components, and a kinship matrix. Using TOPMed as a reference panel, we imputed genotypes in 12 CHARGE studies. Association analyses in CHARGE were conducted separately within each study and stratified by ancestry group. Our primary analysis consisted of a meta-analysis of TOPMed and CHARGE (N=35,006 for FVIII and N=35,362 for vWF).

Results: We identified associations (P< 5E-9) with variants at 11 known loci for FVIII and 12 for vWF, of which 10 overlapped. Additionally, 4 new loci were associated with FVIII (F12, KNG1, ASGR1, and CD36). F12 and KNG1 encode kininogen 1 and factor XII, which are both involved in the contact activation pathway that FVIII also participates in. Variants at F12 and KNG1 were not associated with vWF (P>0.05). At the ASGR1 locus, top variant rs62061426 is associated with ASGR1 expression in liver. ASGR1 encodes a protein that degrades glycoproteins like FVIII and vWF. Consistent with this, the ASGR1-decreasing allele is associated with increased levels of FVIII. The driving variant in CD36, rs3211938, is a loss-of-function variant that causes CD36 deficiency and is associated with other hematological phenotypes. The loss-of-function allele was only found among the African ancestry participants (frequency = 11.6%). Top variants at ASGR1 and CD36 were suggestively associated with vWF (P<0.05).

Conclusions: Four new loci were identified for FVIII, including 2 loci that were independent of vWF.