Genome-Wide Association Studies of MRI-Defined Brain Infarcts
Author:
Debette Stéphanie1, Bis Joshua C.1, Fornage Myriam1, Schmidt Helena1, Ikram M. Arfan1, Sigurdsson Sigurdur1, Heiss Gerardo1, Struchalin Maksim1, Smith Albert V.1, van der Lugt Aad1, DeCarli Charles1, Lumley Thomas1, Knopman David S.1, Enzinger Christian1, Eiriksdottir Gudny1, Koudstaal Peter J.1, DeStefano Anita L.1, Psaty Bruce M.1, Dufouil Carole1, Catellier Diane J.1, Fazekas Franz1, Aspelund Thor1, Aulchenko Yurii S.1, Beiser Alexa1, Rotter Jerome I.1, Tzourio Christophe1, Shibata Dean K.1, Tscherner Maria1, Harris Tamara B.1, Rivadeneira Fernando1, Atwood Larry D.1, Rice Kenneth1, Gottesman Rebecca F.1, van Buchem Mark A.1, Uitterlinden Andre G.1, Kelly-Hayes Margaret1, Cushman Mary1, Zhu Yicheng1, Boerwinkle Eric1, Gudnason Vilmundur1, Hofman Albert1, Romero Jose R.1, Lopez Oscar1, van Duijn Cornelia M.1, Au Rhoda1, Heckbert Susan R.1, Wolf Philip A.1, Mosley Thomas H.1, Seshadri Sudha1, Breteler Monique M.B.1, Schmidt Reinhold1, Launer Lenore J.1, Longstreth W.T.1
Affiliation:
1. For authors representing the Aging Gene-Environment Susceptibility-Reykjavik Study: From Icelandic Heart Association (S.S., A.S., G.E., T.A., V.G.), Kopavogur, Iceland; Department of Radiology (M.A.v.B.), Leiden University Medical Center, Leiden, The Netherlands; University of Iceland (T.A., V.G.), Reykjavik, Iceland; Intramural Research Program, Laboratory of Epidemiology, Demography, and Biometry (L.J.L., T.B.H.), National Institute of Aging, Bethesda, Md. For authors representing the...
Abstract
Background and Purpose—
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 ≥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
=4.64×10
−7
). Highly suggestive associations (
P
<1.0×10
−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.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Advanced and Specialized Nursing,Cardiology and Cardiovascular Medicine,Neurology (clinical)
Cited by
81 articles.
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