Genome-Wide Association Transethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels.

TitleGenome-Wide Association Transethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels.
Publication TypeJournal Article
Year of Publication2019
AuthorsSabater-Lleal, M, Huffman, JE, de Vries, PS, Marten, J, Mastrangelo, MA, Song, C, Pankratz, N, Ward-Caviness, CK, Yanek, LR, Trompet, S, Delgado, GE, Guo, X, Bartz, TM, Martinez-Perez, A, Germain, M, de Haan, HG, Ozel, AB, Polasek, O, Smith, AV, Eicher, JD, Reiner, AP, Tang, W, Davies, NM, Stott, DJ, Rotter, JI, Tofler, GH, Boerwinkle, E, de Maat, MPM, Kleber, ME, Welsh, P, Brody, JA, Chen, M-H, Vaidya, D, Soria, JManuel, Suchon, P, Vlieg, Avan Hylcka, Desch, KC, Kolcic, I, Joshi, PK, Launer, LJ, Harris, TB, Campbell, H, Rudan, I, Becker, DM, Li, JZ, Rivadeneira, F, Uitterlinden, AG, Hofman, A, Franco, OH, Cushman, M, Psaty, BM, Morange, P-E, McKnight, B, Chong, MR, Fernandez-Cadenas, I, Rosand, J, Lindgren, A, Gudnason, V, Wilson, JF, Hayward, C, Ginsburg, D, Fornage, M, Rosendaal, FR, Souto, JCarlos, Becker, LC, Jenny, NS, Marz, W, J Jukema, W, Dehghan, A, Trégouët, D-A, Morrison, AC, Johnson, AD, O'Donnell, CJ, Strachan, DP, Lowenstein, CJ, Smith, NL
Corporate AuthorsINVENT Consortium; MEGASTROKE Consortium of the International Stroke Genetics Consortium (ISGC)
Date Published2019 Jan 29
KeywordsArterial Occlusive Diseases, Biomarkers, Blood Coagulation, Blood Coagulation Disorders, Inherited, Factor VIII, Genetic Loci, Genetic Markers, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Mendelian Randomization Analysis, Phenotype, Ribosomal Protein L3, Risk Factors, Venous Thrombosis, von Willebrand Factor

BACKGROUND: Factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are associated with risk of arterial and venous thrombosis and with hemorrhagic disorders. We aimed to identify and functionally test novel genetic associations regulating plasma FVIII and VWF.

METHODS: We meta-analyzed genome-wide association results from 46 354 individuals of European, African, East Asian, and Hispanic ancestry. All studies performed linear regression analysis using an additive genetic model and associated ≈35 million imputed variants with natural log-transformed phenotype levels. In vitro gene silencing in cultured endothelial cells was performed for candidate genes to provide additional evidence on association and function. Two-sample Mendelian randomization analyses were applied to test the causal role of FVIII and VWF plasma levels on the risk of arterial and venous thrombotic events.

RESULTS: We identified 13 novel genome-wide significant ( P≤2.5×10) associations, 7 with FVIII levels ( FCHO2/TMEM171/TNPO1, HLA, SOX17/RP1, LINC00583/NFIB, RAB5C-KAT2A, RPL3/TAB1/SYNGR1, and ARSA) and 11 with VWF levels ( PDHB/PXK/KCTD6, SLC39A8, FCHO2/TMEM171/TNPO1, HLA, GIMAP7/GIMAP4, OR13C5/NIPSNAP, DAB2IP, C2CD4B, RAB5C-KAT2A, TAB1/SYNGR1, and ARSA), beyond 10 previously reported associations with these phenotypes. Functional validation provided further evidence of association for all loci on VWF except ARSA and DAB2IP. Mendelian randomization suggested causal effects of plasma FVIII activity levels on venous thrombosis and coronary artery disease risk and plasma VWF levels on ischemic stroke risk.

CONCLUSIONS: The meta-analysis identified 13 novel genetic loci regulating FVIII and VWF plasma levels, 10 of which we validated functionally. We provide some evidence for a causal role of these proteins in thrombotic events.

Alternate JournalCirculation
PubMed ID30586737
PubMed Central IDPMC6438386
Grant ListUH3 NS100605 / NS / NINDS NIH HHS / United States
R01 NS017950 / NS / NINDS NIH HHS / United States
R35 HL135793 / HL / NHLBI NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
P30 AG010129 / AG / NIA NIH HHS / United States
R01 AG054076 / AG / NIA NIH HHS / United States
R01 HL120393 / HL / NHLBI NIH HHS / United States
R01 HL059367 / HL / NHLBI NIH HHS / United States
U01 HL130114 / HL / NHLBI NIH HHS / United States
U01 HL120393 / HL / NHLBI NIH HHS / United States
Z99 AG999999 / ImNIH / Intramural NIH HHS / United States
Z01 AG007380-02 / ImNIH / Intramural NIH HHS / United States
MC_UU_00007/10 / MRC_ / Medical Research Council / United Kingdom
U01 AG052409 / AG / NIA NIH HHS / United States
R01 HL134894 / HL / NHLBI NIH HHS / United States
U01 AG049505 / AG / NIA NIH HHS / United States

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