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

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 &lt; 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.