Genome-wide association studies of MRI-defined brain infarcts: meta-analysis from the CHARGE Consortium.
Debette S., Bis JC., Fornage M., Schmidt H., Ikram MA., Sigurdsson S., Heiss G., Struchalin M., Smith AV., van der Lugt A., DeCarli C., Lumley T., Knopman DS., Enzinger C., Eiriksdottir G., Koudstaal PJ., DeStefano AL., Psaty BM., Dufouil C., Catellier DJ., Fazekas F., Aspelund T., Aulchenko YS., Beiser A., Rotter JI., Tzourio C., Shibata DK., Tscherner M., Harris TB., Rivadeneira F., Atwood LD., Rice K., Gottesman RF., van Buchem MA., Uitterlinden AG., Kelly-Hayes M., Cushman M., Zhu Y., Boerwinkle E., Gudnason V., Hofman A., Romero JR., Lopez O., van Duijn CM., Au R., Heckbert SR., Wolf PA., Mosley TH., Seshadri S., Breteler MMB., Schmidt R., Launer LJ., Longstreth WT.
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 >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.