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.
Smith
Nicholas L
NL
Department of Epidemiology, University of Washington, Seattle, Wash 98101, USA. nlsmith@u.washington.edu
Chen
Ming-Huei
MH
Dehghan
Abbas
A
Strachan
David P
DP
Basu
Saonli
S
Soranzo
Nicole
N
Hayward
Caroline
C
Rudan
Igor
I
Sabater-Lleal
Maria
M
Bis
Joshua C
JC
de Maat
Moniek P M
MP
Rumley
Ann
A
Kong
Xiaoxiao
X
Yang
Qiong
Q
Williams
Frances M K
FM
Vitart
Veronique
V
Campbell
Harry
H
Mälarstig
Anders
A
Wiggins
Kerri L
KL
Van Duijn
Cornelia M
CM
McArdle
Wendy L
WL
Pankow
James S
JS
Johnson
Andrew D
AD
Silveira
Angela
A
McKnight
Barbara
B
Uitterlinden
Andre G
AG
Aleksic
Nena
N
Meigs
James B
JB
Peters
Annette
A
Koenig
Wolfgang
W
Cushman
Mary
M
Kathiresan
Sekar
S
Rotter
Jerome I
JI
Bovill
Edwin G
EG
Hofman
Albert
A
Boerwinkle
Eric
E
Tofler
Geoffrey H
GH
Peden
John F
JF
Psaty
Bruce M
BM
Leebeek
Frank
F
Folsom
Aaron R
AR
Larson
Martin G
MG
Spector
Timothy D
TD
Wright
Alan F
AF
Wilson
James F
JF
Hamsten
Anders
A
Lumley
Thomas
T
Witteman
Jacqueline C M
JC
Tang
Weihong
W
O'Donnell
Christopher J
CJ
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