Genome-Wide Association Transethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels
Authors: Sabater-Lleal Maria , Huffman Jennifer E. , de Vries Paul S. , Marten Jonathan , Mastrangelo Michael A. , Song Ci , Pankratz Nathan , Ward-Caviness Cavin K. , Yanek Lisa R. , Trompet Stella , Delgado Graciela E. , Guo Xiuqing , Bartz Traci M. , Martinez-Perez Angel , Germain Marine , de Haan Hugoline G. , Ozel Ayse B. , Polasek Ozren , Smith Albert V. , Eicher John D. , Reiner Alex P. , Tang Weihong , Davies Neil M. , Stott David J. , Rotter Jerome I. , Tofler Geoffrey H. , Boerwinkle Eric , de Maat Moniek P.M. , Kleber Marcus E. , Welsh Paul , Brody Jennifer A. , Chen Ming-Huei , Vaidya Dhananjay , Soria José Manuel , Suchon Pierre , van Hylckama Vlieg Astrid , Desch Karl C. , Kolcic Ivana , Joshi Peter K. , Launer Lenore J. , Harris Tamara B. , Campbell Harry , Rudan Igor , Becker Diane M. , Li Jun Z. , Rivadeneira Fernando , Uitterlinden André G. , Hofman Albert , Franco Oscar H. , Cushman Mary , Psaty Bruce M. , Morange Pierre-Emmanuel , McKnight Barbara , Chong Michael R. , Fernandez-Cadenas Israel , Rosand Jonathan , Lindgren Arne ,   INVENT Consortium; MEGASTROKE Consortium of the International Stroke Genetics Consortium (ISGC), Gudnason Vilmundur , Wilson James F. , Hayward Caroline , Ginsburg David , Fornage Myriam , Rosendaal Frits R. , Souto Juan Carlos , Becker Lewis C. , Jenny Nancy S. , März Winfried , Jukema J. Wouter , Dehghan Abbas , Trégouët David-Alexandre , Morrison Alanna C. , Johnson Andrew D. , O’Donnell Christopher J. , Strachan David P. , Lowenstein Charles J. , Smith Nicholas L. 
Published: January 2019

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.