Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants.
We conducted a genome-wide association study testing single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) for association with early-onset myocardial infarction in 2,967 cases and 3,075 controls. We carried out replication in an independent sample with an effective sample size of up to 19,492. SNPs at nine loci reached genome-wide significance: three are newly identified (21q22 near MRPS6-SLC5A3-KCNE2, 6p24 in PHACTR1 and 2q33 in WDR12) and six replicated prior observations (9p21, 1p13 near CELSR2-PSRC1-SORT1, 10q11 near CXCL12, 1q41 in MIA3, 19p13 near LDLR and 1p32 near PCSK9). We tested 554 common copy number polymorphisms (>1% allele frequency) and none met the pre-specified threshold for replication (P < 10(-3)). We identified 8,065 rare CNVs but did not detect a greater CNV burden in cases compared to controls, in genes compared to the genome as a whole, or at any individual locus. SNPs at nine loci were reproducibly associated with myocardial infarction, but tests of common and rare CNVs failed to identify additional associations with myocardial infarction risk.
Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. skathiresan1@partners.org
Kathiresan
Sekar
S
Voight
Benjamin F
BF
Purcell
Shaun
S
Musunuru
Kiran
K
Ardissino
Diego
D
Mannucci
Pier M
PM
Anand
Sonia
S
Engert
James C
JC
Samani
Nilesh J
NJ
Schunkert
Heribert
H
Erdmann
Jeanette
J
Reilly
Muredach P
MP
Rader
Daniel J
DJ
Morgan
Thomas
T
Spertus
John A
JA
Stoll
Monika
M
Girelli
Domenico
D
McKeown
Pascal P
PP
Patterson
Chris C
CC
Siscovick
David S
DS
O'Donnell
Christopher J
CJ
Elosua
Roberto
R
Peltonen
Leena
L
Salomaa
Veikko
V
Schwartz
Stephen M
SM
Melander
Olle
O
Altshuler
David
D
Ardissino
Diego
D
Merlini
Pier Angelica
PA
Berzuini
Carlo
C
Bernardinelli
Luisa
L
Peyvandi
Flora
F
Tubaro
Marco
M
Celli
Patrizia
P
Ferrario
Maurizio
M
Fetiveau
Raffaela
R
Marziliano
Nicola
N
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Giorgio
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Michele
M
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Flavio
F
Rossi
Marco
M
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Francesco
F
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Alberto
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Stephen M
SM
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David S
DS
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Jean
J
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Yechiel
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Jaume
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G
Subirana
Isaac
I
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Joan
J
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R
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James B
JB
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Gordon
G
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DM
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CA
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V
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Joel N
JN
Asselta
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Stefano
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Mark J
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Benjamin F
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Jeanette
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Wolfgang
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Inke
I
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Christian
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Marcus
M
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Klaus
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Pascal
P
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Chris C
CC
Schunkert
Heribert
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E
Linsel-Nitschke
Patrick
P
Lieb
Wolfgang
W
Ziegler
Andreas
A
König
Inke R
IR
Hengstenberg
Christian
C
Fischer
Marcus
M
Stark
Klaus
K
Grosshennig
Anika
A
Preuss
Michael
M
Wichmann
H-Erich
HE
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H
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JC
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Ron
R
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Changchun
C
Anand
Sonia
S
Kathiresan
Sekar
S
Ardissino
Diego
D
Mannucci
Pier M
PM
Siscovick
David
D
O'Donnell
Christopher J
CJ
Samani
Nilesh J
NJ
Melander
Olle
O
Elosua
Roberto
R
Peltonen
Leena
L
Salomaa
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D
D000328:Adult; D017668:Age of Onset; D000465:Algorithms; D016022:Case-Control Studies; D005260:Female; D018628:Gene Dosage; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000502:physiology; D009203:Myocardial Infarction / Q000453:epidemiology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors