biostudies-literaturede Vries PSNCATS NIH HHSNIEHS NIH HHSNHLBI NIH HHSMedical Research CouncilNNF Center for Basic Metabolic ResearchDanish Diabetes and Endocrine Academy1845-1855https://www.ebi.ac.uk/biostudies/studies/S-EPMC11443575biostudies-literatureUnknown143(18)<h4>Abstract</h4>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 associaBloodA genetic association study of circulating coagulation factor VIII and von Willebrand factor levels.PMC11443575R01 HL131136Hansen GroupMC_UU_00007/10R01 HL134894R01 HL120393P30 ES010126R01 HL117626U01 HL120393HHSN268201800001CR33 HL141791R01 HL139553KL2 TR002490R01 HL172780R01 HL105756PD001-18Ekunwe LPankratz NPsaty BMFaraday NMoissl APRotter JILewis JPKolcic IGuo XJukema JWJohnson ADRosendaal FRBoerwinkle ERich SSDoyle MFMorrison ACStott DJWilson JFLowenstein CJKleber MEHarris SECurran JECarrasquilla GDIkram MARodriguez BATMook-Kanamori DOJoshi PKO'Connell JRHayward CYao JAuer PLBeswick ARaffield LMBartz TMJain DSuchon PKlaric LMorange PEKilpelainen TOSouto JCDeleuze JFCox SRBrody JAMarioni REHeath ASNoordam RDavies GLange LAFornage MTregouet DAYanek LRBecker LCMarz WLinneberg Avan Hylckama Vlieg APolasek OSoria JMDesch KCHuffman JEBlangero JSabater-Lleal MBebo AOsburn WOLi-Gao RBrown MRThibord FSmith NLde Maat MPMRyan KAvan der Harst PTaylor KDMartinez-Perez AGhanbari MReiner APRudan IReventun PArvanitis MWheeler MMTemprano-Sagrera GAlmasy LHoward TEHansen TCampbell HDelgado GEMathias RAOzel ABBen-Shlomo YBrody LCChen MHLe NQKooperberg Cvan Rooij Fde Vries PSTrompet SMitchell BDfalseA genetic association study of circulating coagulation factor VIII and von Willebrand factor levels.<h4>Abstract</h4>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 associa2024-01-01T00:00:00Z2024 May2026-06-02T12:04:28.583Z2025-07-08T03:13:48.035ZS-EPMC114435753832012110.1182/blood.2023021452