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

Maria Sabater-Lleal; Jennifer E. Huffman; Paul S. De Vries; Jonathan Marten; Michael A. Mastrangelo; Ci Song; Nathan Pankratz; Cavin K. Ward-Caviness; Lisa R. Yanek; Stella Trompet; Graciela E. Delgado; Xiuqing Guo; Traci M. Bartz; Angel Martinez-Perez; Marine Germain; Hugoline G. De Haan; Ayse B. Ozel; Ozren Polasek; Albert V. Smith; John D. Eicher; Alex P. Reiner; Weihong Tang; Neil M. Davies; David J. Stott; Jerome I. Rotter; Geoffrey H. Tofler; Eric Boerwinkle; Moniek P.M. De Maat; Marcus E. Kleber; Paul Welsh; Jennifer A. Brody; Ming Huei Chen; Dhananjay Vaidya; José Manuel Soria; Pierre Suchon; Astrid Van Hylckama Vlieg; Karl C. Desch; Ivana Kolcic; Peter K. Joshi; Lenore J. Launer; Tamara B. Harris; Harry Campbell; Igor Rudan; Diane M. Becker; Jun Z. Li; Fernando Rivadeneira; André G. Uitterlinden; Albert Hofman; Oscar H. Franco; Mary Cushman; Bruce M. Psaty; Pierre Emmanuel Morange; Barbara Mcknight; Michael R. Chong; Israel Fernandez-Cadenas; Jonathan Rosand; Arne Lindgren; Vilmundur Gudnason; James F. Wilson; Caroline Hayward; David Ginsburg; Myriam Fornage; Frits R. Rosendaal; Juan Carlos Souto; Lewis C. Becker; Nancy S. Jenny; Winfried März; J. Wouter Jukema; Abbas Dehghan; David Alexandre Trégouët; Alanna C. Morrison; Andrew D. Johnson; Christopher J. O'donnell; David P. Strachan; Charles J. Lowenstein; Nicholas L. Smith

doi:10.1161/CIRCULATIONAHA.118.034532

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

Maria Sabater-Lleal, Jennifer E. Huffman, Paul S. De Vries, Jonathan Marten, Michael A. Mastrangelo, Ci Song, Nathan Pankratz, Cavin K. Ward-Caviness, Lisa R. Yanek, Stella Trompet, Graciela E. Delgado, Xiuqing Guo, Traci M. Bartz, Angel Martinez-Perez, Marine Germain, Hugoline G. De Haan, Ayse B. Ozel, Ozren Polasek, Albert V. Smith, John D. EicherAlex P. Reiner, Weihong Tang, Neil M. Davies, David J. Stott, Jerome I. Rotter, Geoffrey H. Tofler, Eric Boerwinkle, Moniek P.M. De Maat, Marcus E. Kleber, Paul Welsh, Jennifer A. Brody, Ming Huei Chen, Dhananjay Vaidya, José Manuel Soria, Pierre Suchon, Astrid Van Hylckama Vlieg, Karl C. Desch, Ivana Kolcic, Peter K. Joshi, Lenore J. Launer, Tamara B. Harris, Harry Campbell, Igor Rudan, Diane M. Becker, Jun Z. Li, Fernando Rivadeneira, André G. Uitterlinden, Albert Hofman, Oscar H. Franco, Mary Cushman, Bruce M. Psaty, Pierre Emmanuel Morange, Barbara Mcknight, Michael R. Chong, Israel Fernandez-Cadenas, Jonathan Rosand, Arne Lindgren, Vilmundur Gudnason, James F. Wilson, Caroline Hayward, David Ginsburg, Myriam Fornage, Frits R. Rosendaal, Juan Carlos Souto, Lewis C. Becker, Nancy S. Jenny, Winfried März, J. Wouter Jukema, Abbas Dehghan, David Alexandre Trégouët, Alanna C. Morrison, Andrew D. Johnson, Christopher J. O'donnell, David P. Strachan, Charles J. Lowenstein, Nicholas L. Smith

Research output: Contribution to journal › Article › peer-review

101 Scopus citations

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 language	English (US)
Pages (from-to)	620-635
Number of pages	16
Journal	Circulation
Volume	139
Issue number	5
DOIs	https://doi.org/10.1161/CIRCULATIONAHA.118.034532
State	Published - Jan 29 2019

Bibliographical note

Funding Information:
This study is supported in part by the National Heart, Lung, and Blood Institute grant HL134894. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the US Department of Health and Human Services. Dr Sabater-Lleal was partially supported by a European Hematology Association-International Society of Thrombosis and Hemostasis Research Fellowship award to study genetic determinants of FVIII and VWF and by the Swedish Heart-Lung Foundation (20160290) and is a recipient of a Miguel Servet contract from the Spanish Ministry of Health (ISCIII CP17/00142). Dr de Vries is supported by American Heart Association grant 17POST33350042. Sources of funding for the specific cohorts can be found in the online-only Data Supplement.

Funding Information:
Dr Psaty serves on the Data Safety and Monitory Board of a clinical trial funded by Zoll LifeCor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Dr Ginsburg reports equity Ownership in Shire, membership on an entity’s Board of Directors or advisory committees in Portola Pharmaceuticals, and a patent in recombinant VWF and recombinant ADAMTS13. Dr März reports grants and personal fees from Amgen, BASF, Sanofi, Siemens Diagnostics, Aegerion Pharmaceuticals, AstraZeneca, Danone Research, Numares, Pfizer, and Hoffmann LaRoche; personal fees from MSD and Alexion; and grants from Abbott Diagnostics. Dr März is employed by SYN-LAB Holding Deutschland GmbH.

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Publisher link

10.1161/CIRCULATIONAHA.118.034532

https://boris.unibe.ch/127374/1/Sabater-Lleal%20Circulation%202019.pdf

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Sabater-Lleal, M., Huffman, J. E., De Vries, P. S., Marten, J., Mastrangelo, M. A., Song, C., Pankratz, N., Ward-Caviness, C. K., Yanek, L. R., Trompet, S., Delgado, G. E., Guo, X., Bartz, T. M., Martinez-Perez, A., Germain, M., De Haan, H. G., Ozel, A. B., Polasek, O., Smith, A. V., ... Smith, N. L. (2019). Genome-Wide Association Transethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and Von Willebrand Factor Plasma Levels. Circulation, 139(5), 620-635. https://doi.org/10.1161/CIRCULATIONAHA.118.034532

Sabater-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, MH, Vaidya, D, Soria, JM, Suchon, P, Van Hylckama Vlieg, A, 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, PE, Mcknight, B, Chong, MR, Fernandez-Cadenas, I, Rosand, J, Lindgren, A, Gudnason, V, Wilson, JF, Hayward, C, Ginsburg, D, Fornage, M, Rosendaal, FR, Souto, JC, Becker, LC, Jenny, NS, März, W, Jukema, JW, Dehghan, A, Trégouët, DA, Morrison, AC, Johnson, AD, O'donnell, CJ, Strachan, DP, Lowenstein, CJ & Smith, NL 2019, 'Genome-Wide Association Transethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and Von Willebrand Factor Plasma Levels', Circulation, vol. 139, no. 5, pp. 620-635. https://doi.org/10.1161/CIRCULATIONAHA.118.034532

@article{c3048fc901224b44bf74aa377fa1efd0,

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 = "Von Willebrand factor, cardiovascular diseases, factor VIII, genetics, genome-wide association studies, risk factors",

author = "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 Yanek, {Lisa R.} 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 Mary Cushman and Psaty, {Bruce M.} and Morange, {Pierre Emmanuel} and Barbara Mcknight and Chong, {Michael R.} and Israel Fernandez-Cadenas and Jonathan Rosand and Arne Lindgren and Vilmundur Gudnason and Wilson, {James F.} and Caroline Hayward and David Ginsburg and Myriam Fornage and Rosendaal, {Frits R.} and Souto, {Juan Carlos} and Becker, {Lewis C.} and Jenny, {Nancy S.} and Winfried M{\"a}rz and Jukema, {J. Wouter} and Abbas Dehghan and Tr{\'e}gou{\"e}t, {David Alexandre} and Morrison, {Alanna C.} and Johnson, {Andrew D.} and O'donnell, {Christopher J.} and Strachan, {David P.} and Lowenstein, {Charles J.} and Smith, {Nicholas L.}",

note = "Funding Information: This study is supported in part by the National Heart, Lung, and Blood Institute grant HL134894. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the US Department of Health and Human Services. Dr Sabater-Lleal was partially supported by a European Hematology Association-International Society of Thrombosis and Hemostasis Research Fellowship award to study genetic determinants of FVIII and VWF and by the Swedish Heart-Lung Foundation (20160290) and is a recipient of a Miguel Servet contract from the Spanish Ministry of Health (ISCIII CP17/00142). Dr de Vries is supported by American Heart Association grant 17POST33350042. Sources of funding for the specific cohorts can be found in the online-only Data Supplement. Funding Information: Dr Psaty serves on the Data Safety and Monitory Board of a clinical trial funded by Zoll LifeCor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Dr Ginsburg reports equity Ownership in Shire, membership on an entity{\textquoteright}s Board of Directors or advisory committees in Portola Pharmaceuticals, and a patent in recombinant VWF and recombinant ADAMTS13. Dr M{\"a}rz reports grants and personal fees from Amgen, BASF, Sanofi, Siemens Diagnostics, Aegerion Pharmaceuticals, AstraZeneca, Danone Research, Numares, Pfizer, and Hoffmann LaRoche; personal fees from MSD and Alexion; and grants from Abbott Diagnostics. Dr M{\"a}rz is employed by SYN-LAB Holding Deutschland GmbH.",

year = "2019",

month = jan,

day = "29",

doi = "10.1161/CIRCULATIONAHA.118.034532",

language = "English (US)",

volume = "139",

pages = "620--635",

journal = "Circulation",

issn = "0009-7322",

publisher = "Lippincott Williams and Wilkins",

number = "5",

}

TY - JOUR

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

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 R.

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 - Cushman, Mary

AU - Psaty, Bruce M.

AU - Morange, Pierre Emmanuel

AU - Mcknight, Barbara

AU - Chong, Michael R.

AU - Fernandez-Cadenas, Israel

AU - Rosand, Jonathan

AU - Lindgren, Arne

AU - Gudnason, Vilmundur

AU - Wilson, James F.

AU - Hayward, Caroline

AU - Ginsburg, David

AU - Fornage, Myriam

AU - Rosendaal, Frits R.

AU - Souto, Juan Carlos

AU - Becker, Lewis C.

AU - Jenny, Nancy S.

AU - März, Winfried

AU - Jukema, J. Wouter

AU - Dehghan, Abbas

AU - Trégouët, David Alexandre

AU - Morrison, Alanna C.

AU - Johnson, Andrew D.

AU - O'donnell, Christopher J.

AU - Strachan, David P.

AU - Lowenstein, Charles J.

AU - Smith, Nicholas L.

N1 - Funding Information: This study is supported in part by the National Heart, Lung, and Blood Institute grant HL134894. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the US Department of Health and Human Services. Dr Sabater-Lleal was partially supported by a European Hematology Association-International Society of Thrombosis and Hemostasis Research Fellowship award to study genetic determinants of FVIII and VWF and by the Swedish Heart-Lung Foundation (20160290) and is a recipient of a Miguel Servet contract from the Spanish Ministry of Health (ISCIII CP17/00142). Dr de Vries is supported by American Heart Association grant 17POST33350042. Sources of funding for the specific cohorts can be found in the online-only Data Supplement. Funding Information: Dr Psaty serves on the Data Safety and Monitory Board of a clinical trial funded by Zoll LifeCor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Dr Ginsburg reports equity Ownership in Shire, membership on an entity’s Board of Directors or advisory committees in Portola Pharmaceuticals, and a patent in recombinant VWF and recombinant ADAMTS13. Dr März reports grants and personal fees from Amgen, BASF, Sanofi, Siemens Diagnostics, Aegerion Pharmaceuticals, AstraZeneca, Danone Research, Numares, Pfizer, and Hoffmann LaRoche; personal fees from MSD and Alexion; and grants from Abbott Diagnostics. Dr März is employed by SYN-LAB Holding Deutschland GmbH.

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 - Von Willebrand factor

KW - cardiovascular diseases

KW - factor VIII

KW - genetics

KW - genome-wide association studies

KW - risk factors

UR - http://www.scopus.com/inward/record.url?scp=85060618199&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85060618199&partnerID=8YFLogxK

U2 - 10.1161/CIRCULATIONAHA.118.034532

DO - 10.1161/CIRCULATIONAHA.118.034532

M3 - Article

C2 - 30586737

AN - SCOPUS:85060618199

SN - 0009-7322

VL - 139

SP - 620

EP - 635

JO - Circulation

JF - Circulation

IS - 5

ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

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