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

INVENT Consortium; MEGASTROKE Consortium of the International Stroke Genetics Consortium (ISGC)

Research output: Contribution to journalArticle

Abstract

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≤2.5×10-8) 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.

Original languageEnglish (US)
Pages (from-to)620-635
Number of pages16
JournalCirculation
Volume139
Issue number5
DOIs
StatePublished - Jan 29 2019

Fingerprint

Factor VIII
Meta-Analysis
von Willebrand Factor
Genome
Venous Thrombosis
Mendelian Randomization Analysis
Hemorrhagic Disorders
Phenotype
Genetic Loci
Genetic Models
Gene Silencing
Random Allocation
Hispanic Americans
Coronary Artery Disease
Cultured Cells
Linear Models
Carrier Proteins
Endothelial Cells
Stroke
Regression Analysis

Keywords

  • cardiovascular diseases
  • factor VIII
  • genetics
  • genome-wide association studies
  • risk factors
  • von Willebrand factor

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Genome-Wide Association Transethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels. / INVENT Consortium; MEGASTROKE Consortium of the International Stroke Genetics Consortium (ISGC).

In: Circulation, Vol. 139, No. 5, 29.01.2019, p. 620-635.

Research output: Contribution to journalArticle

INVENT Consortium; MEGASTROKE Consortium of the International Stroke Genetics Consortium (ISGC). / Genome-Wide Association Transethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels. In: Circulation. 2019 ; Vol. 139, No. 5. pp. 620-635.
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title = "Genome-Wide Association Transethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels",
abstract = "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≤2.5×10-8) 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.",
keywords = "cardiovascular diseases, factor VIII, genetics, genome-wide association studies, risk factors, von Willebrand factor",
author = "{INVENT Consortium; MEGASTROKE Consortium of the International Stroke Genetics Consortium (ISGC)} and Maria Sabater-Lleal and Huffman, {Jennifer E.} and {de Vries}, {Paul S.} and Jonathan Marten and Mastrangelo, {Michael A.} and Ci Song and Nathan Pankratz and Ward-Caviness, {Cavin K.} and Lisa Yanek and Stella Trompet and Delgado, {Graciela E.} and Xiuqing Guo and Bartz, {Traci M.} and Angel Martinez-Perez and Marine Germain and {de Haan}, {Hugoline G.} and Ozel, {Ayse B.} and Ozren Polasek and Smith, {Albert V.} and Eicher, {John D.} and Reiner, {Alex P.} and Weihong Tang and Davies, {Neil M.} and Stott, {David J.} and Rotter, {Jerome I.} and Tofler, {Geoffrey H.} and Eric Boerwinkle and {de Maat}, {Moniek P.M.} and Kleber, {Marcus E.} and Paul Welsh and Brody, {Jennifer A.} and Chen, {Ming Huei} and Dhananjay Vaidya and Soria, {Jos{\'e} Manuel} and Pierre Suchon and {van Hylckama Vlieg}, Astrid and Desch, {Karl C.} and Ivana Kolcic and Joshi, {Peter K.} and Launer, {Lenore J.} and Harris, {Tamara B.} and Harry Campbell and Igor Rudan and Becker, {Diane M} and Li, {Jun Z.} and Fernando Rivadeneira and Uitterlinden, {Andr{\'e} G.} and Albert Hofman and Franco, {Oscar H.} and Lewis Becker",
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TY - JOUR

T1 - Genome-Wide Association Transethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels

AU - INVENT Consortium; MEGASTROKE Consortium of the International Stroke Genetics Consortium (ISGC)

AU - Sabater-Lleal, Maria

AU - Huffman, Jennifer E.

AU - de Vries, Paul S.

AU - Marten, Jonathan

AU - Mastrangelo, Michael A.

AU - Song, Ci

AU - Pankratz, Nathan

AU - Ward-Caviness, Cavin K.

AU - Yanek, Lisa

AU - Trompet, Stella

AU - Delgado, Graciela E.

AU - Guo, Xiuqing

AU - Bartz, Traci M.

AU - Martinez-Perez, Angel

AU - Germain, Marine

AU - de Haan, Hugoline G.

AU - Ozel, Ayse B.

AU - Polasek, Ozren

AU - Smith, Albert V.

AU - Eicher, John D.

AU - Reiner, Alex P.

AU - Tang, Weihong

AU - Davies, Neil M.

AU - Stott, David J.

AU - Rotter, Jerome I.

AU - Tofler, Geoffrey H.

AU - Boerwinkle, Eric

AU - de Maat, Moniek P.M.

AU - Kleber, Marcus E.

AU - Welsh, Paul

AU - Brody, Jennifer A.

AU - Chen, Ming Huei

AU - Vaidya, Dhananjay

AU - Soria, José Manuel

AU - Suchon, Pierre

AU - van Hylckama Vlieg, Astrid

AU - Desch, Karl C.

AU - Kolcic, Ivana

AU - Joshi, Peter K.

AU - Launer, Lenore J.

AU - Harris, Tamara B.

AU - Campbell, Harry

AU - Rudan, Igor

AU - Becker, Diane M

AU - Li, Jun Z.

AU - Rivadeneira, Fernando

AU - Uitterlinden, André G.

AU - Hofman, Albert

AU - Franco, Oscar H.

AU - Becker, Lewis

PY - 2019/1/29

Y1 - 2019/1/29

N2 - 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≤2.5×10-8) 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.

AB - 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≤2.5×10-8) 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.

KW - cardiovascular diseases

KW - factor VIII

KW - genetics

KW - genome-wide association studies

KW - risk factors

KW - von Willebrand factor

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U2 - 10.1161/CIRCULATIONAHA.118.034532

DO - 10.1161/CIRCULATIONAHA.118.034532

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JO - Circulation

JF - Circulation

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