A genetic association study of circulating coagulation factor VIII and von Willebrand factor levels
Creators: name: Thibord, Florian
name: Le, Ngoc-Quynh
name: Brody, Lawrence C.
name: Chen, Ming-Huei
name: Joshi, Peter K.
name: Kooperberg, Charles
name: Kilpeläinen, Tuomas O.
name: Yao, Jie
name: Morrison, Alanna C.
name: Mook-Kanamori, Dennis O.
name: Trégouët, David-Alexandre
name: Noordam, Raymond
name: Ryan, Kathleen A.
name: Boerwinkle, Eric
name: Trans-Omics for Precision Medicine (TOPMed) Program
name: O'Connell, Jeffrey R.
name: Carrasquilla, German D.
name: Davies, Gail
name: Hansen, Torben
name: Cox, Simon R.
name: Johnson, Andrew
name: Delgado, Graciela E.
name: Becker, Lewis C.
name: Rodriguez, Benjamin A. T.
name: van Rooij, Frank
name: Arvanitis, Marios
name: Rudan, Igor
name: Ben-Shlomo, Yoav
name: Marioni, Riccardo E.
name: Deleuze, Jean-François
name: März, Winfried
name: Brody, Jennifer A.
name: Reventun, Paula
name: de Maat, Moniek P. M.
name: Raffield, Laura M.
name: Jain, Deepti
name: Almasy, Laura
name: Kolcic, Ivana
name: Bebo, Allison
name: Psaty, Bruce M.
name: Hayward, Caroline
name: Rich, Stephen S.
name: Osburn, William O.
name: Smith, Albert Vernon
name: Rotter, Jerome
name: Ghanbari, Mohsen
name: Morange, Pierre-Emmanuel
name: Blangero, John
name: Ekunwe, Lynette
name: Ikram, M. Arfan
name: Souto, Juan Carlos
name: Li-Gao, Ruifang
name: Campbell, Harry
name: Lewis, Joshua P.
name: Stott, David J.
name: Reiner, Alex P.
name: Pankratz, Nathan
name: Polasek, Ozren
name: Mitchell, Braxton D.
name: Linneberg, Allan
name: Moissl, Angela P.
name: Temprano-Sagrera, Gerard
name: Soria, Jose Manuel
name: Brown, Michael R.
name: van der Harst, Pim
name: Ozel, Ayse Bilge
name: Klaric, Lucija
name: Huffman, Jennifer E.
name: Wilson, Carla
name: Yanek, Lisa R.
name: Fornage, Myriam
name: Trompet, Stella
name: Desch, Karl C.
name: Lange, Christoph
name: Wheeler, Marsha M.
name: Doyle, Margaret F.
name: Martinez-Perez, Angel
name: Bartz, Traci M.
name: Beswick, Andrew
name: Jukema, J. Wouter
name: van Hylckama Vlieg, Astrid
name: Sabater-Lleal, Maria
name: Harris, Sarah E.
name: Suchon, Pierre
name: Howard, Tom E.
name: Curran, Joanne E.
name: Taylor, Kent D.
name: Auer, Paul L.
name: Faraday, Nauder
name: Mathias, Rasika
name: Kleber, Marcus E.
name: INVENT consortium
name: Guo, Xiuqing
name: Lowenstein, Charles J.
name: de Vries, Paul S.
name: Rosendaal, Frits R.
name: Heath, Adam S.
Publisher: name: American Society of Hematology
Year: 2024

description: Coagulation factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are critical to coagulation and platelet aggregation. We leveraged whole-genome sequence data from the Trans-Omics for Precision Medicine (TOPMed) program along with TOPMed-based imputation of genotypes in additional samples to identify genetic associations with circulating FVIII and VWF levels in a single-variant meta-analysis, including up to 45 289 participants. Gene-based aggregate tests were implemented in TOPMed. We identified 3 candidate causal genes and tested their functional effect on FVIII release from human liver endothelial cells (HLECs) and VWF release from human umbilical vein endothelial cells. Mendelian randomization was also performed to provide evidence for causal associations of FVIII and VWF with thrombotic outcomes. We identified associations (P < 5 × 10-9) at 7 new loci for FVIII (ST3GAL4, CLEC4M, B3GNT2, ASGR1, F12, KNG1, and TREM1/NCR2) and 1 for VWF (B3GNT2). VWF, ABO, and STAB2 were associated with FVIII and VWF in gene-based analyses. Multiphenotype analysis of FVIII and VWF identified another 3 new loci, including PDIA3. Silencing of B3GNT2 and the previously reported CD36 gene decreased release of FVIII by HLECs, whereas silencing of B3GNT2, CD36, and PDIA3 decreased release of VWF by HVECs. Mendelian randomization supports causal association of higher FVIII and VWF with increased risk of thrombotic outcomes. Seven new loci were identified for FVIII and 1 for VWF, with evidence supporting causal associations of FVIII and VWF with thrombotic outcomes. B3GNT2, CD36, and PDIA3 modulate the release of FVIII and/or VWF in vitro.