Genome-wide association studies of MRI-defined brain infarcts: meta-analysis from the CHARGE Consortium.
OBJECTIVE
Previous studies examining genetic associations with MRI-defined brain infarct have yielded inconsistent findings. We investigated genetic variation underlying covert MRI infarct in persons without histories of transient ischemic attack or stroke. We performed meta-analysis of genome-wide association studies of white participants in 6 studies comprising the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.


METHODS
Using 2.2 million genotyped and imputed single nucleotide polymorphisms, each study performed cross-sectional genome-wide association analysis of MRI infarct using age- and sex-adjusted logistic regression models. Study-specific findings were combined in an inverse-variance-weighted meta-analysis, including 9401 participants with mean age 69.7 (19.4% of whom had >or=1 MRI infarct).


RESULTS
The most significant association was found with rs2208454 (minor allele frequency, 20%), located in intron 3 of MACRO domain containing 2 gene and in the downstream region of fibronectin leucine-rich transmembrane protein 3 gene. Each copy of the minor allele was associated with lower risk of MRI infarcts (odds ratio, 0.76; 95% confidence interval, 0.68-0.84; P=4.64x10(-7)). Highly suggestive associations (P<1.0x10(-5)) were also found for 22 other single nucleotide polymorphisms in linkage disequilibrium (r(2)>0.64) with rs2208454. The association with rs2208454 did not replicate in independent samples of 1822 white and 644 black participants, although 4 single nucleotide polymorphisms within 200 kb from rs2208454 were associated with MRI infarcts in the black population sample.


CONCLUSIONS
This first community-based, genome-wide association study on covert MRI infarcts uncovered novel associations. Although replication of the association with top single nucleotide polymorphisms failed, possibly because of insufficient power, results in the black population sample are encouraging, and further efforts at replication are needed.
Debette
Stéphanie
S
Department of Neurology, Boston University School of Medicine, Boston, Mass, USA.
Bis
Joshua C
JC
Fornage
Myriam
M
Schmidt
Helena
H
Ikram
M Arfan
MA
Sigurdsson
Sigurdur
S
Heiss
Gerardo
G
Struchalin
Maksim
M
Smith
Albert V
AV
van der Lugt
Aad
A
DeCarli
Charles
C
Lumley
Thomas
T
Knopman
David S
DS
Enzinger
Christian
C
Eiriksdottir
Gudny
G
Koudstaal
Peter J
PJ
DeStefano
Anita L
AL
Psaty
Bruce M
BM
Dufouil
Carole
C
Catellier
Diane J
DJ
Fazekas
Franz
F
Aspelund
Thor
T
Aulchenko
Yurii S
YS
Beiser
Alexa
A
Rotter
Jerome I
JI
Tzourio
Christophe
C
Shibata
Dean K
DK
Tscherner
Maria
M
Harris
Tamara B
TB
Rivadeneira
Fernando
F
Atwood
Larry D
LD
Rice
Kenneth
K
Gottesman
Rebecca F
RF
van Buchem
Mark A
MA
Uitterlinden
Andre G
AG
Kelly-Hayes
Margaret
M
Cushman
Mary
M
Zhu
Yicheng
Y
Boerwinkle
Eric
E
Gudnason
Vilmundur
V
Hofman
Albert
A
Romero
Jose R
JR
Lopez
Oscar
O
van Duijn
Cornelia M
CM
Au
Rhoda
R
Heckbert
Susan R
SR
Wolf
Philip A
PA
Mosley
Thomas H
TH
Seshadri
Sudha
S
Breteler
Monique M B
MM
Schmidt
Reinhold
R
Launer
Lenore J
LJ
Longstreth
W T
WT
D001741:Black or African American / Q000235:genetics; D000368:Aged; D001921:Brain / Q000473:pathology* / Q000503:physiopathology; D020520:Brain Infarction / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D014644:Genetic Variation / Q000235:genetics; D055106:Genome-Wide Association Study / Q000706:statistics & numerical data*; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011446:Prospective Studies
D005819:Genetic Markers