Genomewide association analysis of coronary artery disease.
BACKGROUND
Modern genotyping platforms permit a systematic search for inherited components of complex diseases. We performed a joint analysis of two genomewide association studies of coronary artery disease.


METHODS
We first identified chromosomal loci that were strongly associated with coronary artery disease in the Wellcome Trust Case Control Consortium (WTCCC) study (which involved 1926 case subjects with coronary artery disease and 2938 controls) and looked for replication in the German MI [Myocardial Infarction] Family Study (which involved 875 case subjects with myocardial infarction and 1644 controls). Data on other single-nucleotide polymorphisms (SNPs) that were significantly associated with coronary artery disease in either study (P<0.001) were then combined to identify additional loci with a high probability of true association. Genotyping in both studies was performed with the use of the GeneChip Human Mapping 500K Array Set (Affymetrix).


RESULTS
Of thousands of chromosomal loci studied, the same locus had the strongest association with coronary artery disease in both the WTCCC and the German studies: chromosome 9p21.3 (SNP, rs1333049) (P=1.80x10(-14) and P=3.40x10(-6), respectively). Overall, the WTCCC study revealed nine loci that were strongly associated with coronary artery disease (P<1.2x10(-5) and less than a 50% chance of being falsely positive). In addition to chromosome 9p21.3, two of these loci were successfully replicated (adjusted P<0.05) in the German study: chromosome 6q25.1 (rs6922269) and chromosome 2q36.3 (rs2943634). The combined analysis of the two studies identified four additional loci significantly associated with coronary artery disease (P<1.3x10(-6)) and a high probability (>80%) of a true association: chromosomes 1p13.3 (rs599839), 1q41 (rs17465637), 10q11.21 (rs501120), and 15q22.33 (rs17228212).


CONCLUSIONS
We identified several genetic loci that, individually and in aggregate, substantially affect the risk of development of coronary artery disease.
Samani
Nilesh J
NJ
University of Leicester, Leicester, United Kingdom. njs@le.ac.uk
Erdmann
Jeanette
J
Hall
Alistair S
AS
Hengstenberg
Christian
C
Mangino
Massimo
M
Mayer
Bjoern
B
Dixon
Richard J
RJ
Meitinger
Thomas
T
Braund
Peter
P
Wichmann
H-Erich
HE
Barrett
Jennifer H
JH
König
Inke R
IR
Stevens
Suzanne E
SE
Szymczak
Silke
S
Tregouet
David-Alexandre
DA
Iles
Mark M
MM
Pahlke
Friedrich
F
Pollard
Helen
H
Lieb
Wolfgang
W
Cambien
Francois
F
Fischer
Marcus
M
Ouwehand
Willem
W
Blankenberg
Stefan
S
Balmforth
Anthony J
AJ
Baessler
Andrea
A
Ball
Stephen G
SG
Strom
Tim M
TM
Braenne
Ingrid
I
Gieger
Christian
C
Deloukas
Panos
P
Tobin
Martin D
MD
Ziegler
Andreas
A
Thompson
John R
JR
Schunkert
Heribert
H
D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D003324:Coronary Artery Disease / Q000235:genetics*; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012306:Risk
D005819:Genetic Markers