Genetic variants associated with cardiac structure and function: a meta-analysis and replication of genome-wide association data.
BACKGROUND
Echocardiographic measures of left ventricular (LV) structure and function are heritable phenotypes of cardiovascular disease.


OBJECTIVE
To identify common genetic variants associated with cardiac structure and function by conducting a meta-analysis of genome-wide association data in 5 population-based cohort studies (stage 1) with replication (stage 2) in 2 other community-based samples.


METHODS
Within each of 5 community-based cohorts comprising the EchoGen consortium (stage 1; n = 12 612 individuals of European ancestry; 55% women, aged 26-95 years; examinations between 1978-2008), we estimated the association between approximately 2.5 million single-nucleotide polymorphisms (SNPs; imputed to the HapMap CEU panel) and echocardiographic traits. In stage 2, SNPs significantly associated with traits in stage 1 were tested for association in 2 other cohorts (n = 4094 people of European ancestry). Using a prespecified P value threshold of 5 x 10(-7) to indicate genome-wide significance, we performed an inverse variance-weighted fixed-effects meta-analysis of genome-wide association data from each cohort.


METHODS
Echocardiographic traits: LV mass, internal dimensions, wall thickness, systolic dysfunction, aortic root, and left atrial size.


RESULTS
In stage 1, 16 genetic loci were associated with 5 echocardiographic traits: 1 each with LV internal dimensions and systolic dysfunction, 3 each with LV mass and wall thickness, and 8 with aortic root size. In stage 2, 5 loci replicated (6q22 locus associated with LV diastolic dimensions, explaining <1% of trait variance; 5q23, 12p12, 12q14, and 17p13 associated with aortic root size, explaining 1%-3% of trait variance).


CONCLUSIONS
We identified 5 genetic loci harboring common variants that were associated with variation in LV diastolic dimensions and aortic root size, but such findings explained a very small proportion of variance. Further studies are required to replicate these findings, identify the causal variants at or near these loci, characterize their functional significance, and determine whether they are related to overt cardiovascular disease.
Vasan
Ramachandran S
RS
Framingham Heart Study, 73 Mt Wayte Ave, Ste 2, Framingham, MA 01702-5827, USA. vasan@bu.edu
Glazer
Nicole L
NL
Felix
Janine F
JF
Lieb
Wolfgang
W
Wild
Philipp S
PS
Felix
Stephan B
SB
Watzinger
Norbert
N
Larson
Martin G
MG
Smith
Nicholas L
NL
Dehghan
Abbas
A
Grosshennig
Anika
A
Schillert
Arne
A
Teumer
Alexander
A
Schmidt
Reinhold
R
Kathiresan
Sekar
S
Lumley
Thomas
T
Aulchenko
Yurii S
YS
König
Inke R
IR
Zeller
Tanja
T
Homuth
Georg
G
Struchalin
Maksim
M
Aragam
Jayashri
J
Bis
Joshua C
JC
Rivadeneira
Fernando
F
Erdmann
Jeanette
J
Schnabel
Renate B
RB
Dörr
Marcus
M
Zweiker
Robert
R
Lind
Lars
L
Rodeheffer
Richard J
RJ
Greiser
Karin Halina
KH
Levy
Daniel
D
Haritunians
Talin
T
Deckers
Jaap W
JW
Stritzke
Jan
J
Lackner
Karl J
KJ
Völker
Uwe
U
Ingelsson
Erik
E
Kullo
Iftikhar
I
Haerting
Johannes
J
O'Donnell
Christopher J
CJ
Heckbert
Susan R
SR
Stricker
Bruno H
BH
Ziegler
Andreas
A
Reffelmann
Thorsten
T
Redfield
Margaret M
MM
Werdan
Karl
K
Mitchell
Gary F
GF
Rice
Kenneth
K
Arnett
Donna K
DK
Hofman
Albert
A
Gottdiener
John S
JS
Uitterlinden
Andre G
AG
Meitinger
Thomas
T
Blettner
Maria
M
Friedrich
Nele
N
Wang
Thomas J
TJ
Psaty
Bruce M
BM
van Duijn
Cornelia M
CM
Wichmann
H-Erich
HE
Munzel
Thomas F
TF
Kroemer
Heyo K
HK
Benjamin
Emelia J
EJ
Rotter
Jerome I
JI
Witteman
Jacqueline C
JC
Schunkert
Heribert
H
Schmidt
Helena
H
Völzke
Henry
H
Blankenberg
Stefan
S
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001011:Aorta / Q000033:anatomy & histology; D002318:Cardiovascular Diseases / Q000453:epidemiology* / Q000235:genetics; D004452:Echocardiography; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006325:Heart Atria / Q000033:anatomy & histology; D006352:Heart Ventricles / Q000033:anatomy & histology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009929:Organ Size; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D018487:Ventricular Dysfunction, Left / Q000235:genetics; D016277:Ventricular Function, Left / Q000235:genetics*; D044465:White People