Genome-wide association studies of MRI-defined brain infarcts: meta-analysis from the CHARGE Consortium

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 >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.

Keywords: MRI; brain infarction; cohort study; genome-wide association study; meta-analysis.

Figure 1

Genome-wide signal intensity (Manhattan) plot showing individual p-values against their genomic position for covert MRI-defined brain infarcts. Within each chromosome (x-axis), results are plotted left to right from p-terminal end. Solid black line indicates preset threshold for genome-wide significance, p=5.0×10⁻⁸; dashed blue line, more liberal threshold for genome-wide significance also used in the literature, p=5.0×10⁻⁷; dotted red line, threshold for highly suggestive associations, p=1.0×10⁻⁵.

Figure 2

Forest plot for top hit (rs2208454). Individual studies are plotted against individual effect sizes (odds ratios). Size of blue boxes is inversely proportional to variance. Horizontal lines are 95% confidence intervals.

Figure 3

Regional plot for associations in region centered on top hit. All SNPs (triangles) are plotted with their meta-analysis p-values against their genomic position. The color of the triangles represents the linkage disequilibrium between SNPs: purple: r²≤0.05, light blue: 0.05<r²≤0.10, green: 0.10<r²≤0.30, yellow: 0.30<r²≤0.60, orange: 0.60<r²≤0.80, red: r²>0.80. Light blue line represents estimated recombination rates. Genes are shown as dark green arrows.

Figure 4

Linkage disequilibrium (LD) plot of region in MACROD2 including top hit (rs2208454), 22 other SNPs with p<10⁻⁵ in meta-analysis, and 4 SNPs with p<0.05 in African-American sample, using HapMap release 22. Plot on top depicts LD in European population (CEU) while plot on bottom depicts LD in African population (YRI). The color scheme is white for D’<1 and LOD<2, blue for D’=1 and LOD<2, shades of pink and red for D’<1 and LOD≥2, and bright red for D’=1 and LOD≥2. The SNP marked in red is rs2208454, the 4 SNPs marked in blue are SNPs with p<0.05 in African-American sample, from left to right: rs7268327, rs1998237, rs4464346, rs8116105. LD could not be measured for 3 SNPs in the YRI population because of a minor allele frequency <0.001 (rs6135125, rs6110247, rs12624446). Green lines represent genes in region.