Novel associations of multiple genetic loci with plasma levels of factor VII, factor VIII, and von Willebrand factor: The CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) Consortium.
BACKGROUND
Plasma levels of coagulation factors VII (FVII), VIII (FVIII), and von Willebrand factor (vWF) influence risk of hemorrhage and thrombosis. We conducted genome-wide association studies to identify new loci associated with plasma levels.


RESULTS
The setting of the study included 5 community-based studies for discovery comprising 23 608 European-ancestry participants: Atherosclerosis Risk In Communities Study, Cardiovascular Health Study, British 1958 Birth Cohort, Framingham Heart Study, and Rotterdam Study. All subjects had genome-wide single-nucleotide polymorphism (SNP) scans and at least 1 phenotype measured: FVII activity/antigen, FVIII activity, and vWF antigen. Each study used its genotype data to impute to HapMap SNPs and independently conducted association analyses of hemostasis measures using an additive genetic model. Study findings were combined by meta-analysis. Replication was conducted in 7604 participants not in the discovery cohort. For FVII, 305 SNPs exceeded the genome-wide significance threshold of 5.0x10(-8) and comprised 5 loci on 5 chromosomes: 2p23 (smallest P value 6.2x10(-24)), 4q25 (3.6x10(-12)), 11q12 (2.0x10(-10)), 13q34 (9.0x10(-259)), and 20q11.2 (5.7x10(-37)). Loci were within or near genes, including 4 new candidate genes and F7 (13q34). For vWF, 400 SNPs exceeded the threshold and marked 8 loci on 6 chromosomes: 6q24 (1.2x10(-22)), 8p21 (1.3x10(-16)), 9q34 (<5.0x10(-324)), 12p13 (1.7x10(-32)), 12q23 (7.3x10(-10)), 12q24.3 (3.8x10(-11)), 14q32 (2.3x10(-10)), and 19p13.2 (1.3x10(-9)). All loci were within genes, including 6 new candidate genes, as well as ABO (9q34) and VWF (12p13). For FVIII, 5 loci were identified and overlapped vWF findings. Nine of the 10 new findings were replicated.


CONCLUSIONS
New genetic associations were discovered outside previously known biological pathways and may point to novel prevention and treatment targets of hemostasis disorders.
Department of Epidemiology, University of Washington, Seattle, Wash 98101, USA. nlsmith@u.washington.edu
Nicholas L
NL
Smith
Ming-Huei
MH
Chen
Abbas
A
Dehghan
David P
DP
Strachan
Saonli
S
Basu
Nicole
N
Soranzo
Caroline
C
Hayward
Igor
I
Rudan
Maria
M
Sabater-Lleal
Joshua C
JC
Bis
Moniek P M
MP
de Maat
Ann
A
Rumley
Xiaoxiao
X
Kong
Qiong
Q
Yang
Frances M K
FM
Williams
Veronique
V
Vitart
Harry
H
Campbell
Anders
A
Mälarstig
Kerri L
KL
Wiggins
Cornelia M
CM
Van Duijn
Wendy L
WL
McArdle
James S
JS
Pankow
Andrew D
AD
Johnson
Angela
A
Silveira
Barbara
B
McKnight
Andre G
AG
Uitterlinden
Nena
N
Aleksic
James B
JB
Meigs
Annette
A
Peters
Wolfgang
W
Koenig
Mary
M
Cushman
Sekar
S
Kathiresan
Jerome I
JI
Rotter
Edwin G
EG
Bovill
Albert
A
Hofman
Eric
E
Boerwinkle
Geoffrey H
GH
Tofler
John F
JF
Peden
Bruce M
BM
Psaty
Frank
F
Leebeek
Aaron R
AR
Folsom
Martin G
MG
Larson
Timothy D
TD
Spector
Alan F
AF
Wright
James F
JF
Wilson
Anders
A
Hamsten
Thomas
T
Lumley
Jacqueline C M
JC
Witteman
Weihong
W
Tang
Christopher J
CJ
O'Donnell
D000328:Adult; D005167:Factor VII / Q000032:analysis / Q000235:genetics*; D005169:Factor VIII / Q000032:analysis / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D006487:Hemostasis / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D013927:Thrombosis / Q000453:epidemiology / Q000235:genetics; D014841:von Willebrand Factor / Q000032:analysis / Q000235:genetics*
D014841:von Willebrand Factor; D005167:Factor VII; D005169:Factor VIII