Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque

Abstract

Carotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 × 10(-8)). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events.

Figure 1. A–B: Genome-wide Manhattan plots for common cIMT and plaque

Plots show the individual p-values (based on discovery meta-analysis) against their genomic position for common carotid IMT (Figure 1A), the presence of plaque (Figure 1B). Within each chromosome, shown on the x-axis, the results are plotted left to right from the p-terminal end. The dashed line indicates the threshold for follow-up, p<4 ×10⁻⁷ and the solid line indicates the threshold for genome-wide significance, p<4 ×10⁻⁸. The nearest genes are indicated above points that surpassed our genome-wide significance threshold; genes that are greater than 100 kb from the signal SNP are indicated in parentheses.

Figure 2. Regional plots for common carotid IMT SNPs

Plots are centered on the most significant SNP at locus along with the meta-analysis results for SNPs in the 100kb region surrounding it. All SNPs are plotted with their discovery meta-analysis p-values against their genomic position, with the most significant SNP in the region indicated as a diamond and other SNPs shaded according to their pairwise correlation (r²) with the signal SNP. The light blue line represents the estimated recombination rates. Gene annotations are shown as dark green lines.

Figure 3. Regional plots for plaque SNPs

Plots are centered on the most significant SNP at each locus along with the meta-analysis results for SNPs in the 100kb region surrounding it. All SNPs are plotted with their discovery meta-analysis p-values against their genomic position, with the most significant SNP in the region indicated as a diamond and other SNPs shaded according to their pairwise correlation (r²) with the signal SNP. The light blue line represents the estimated recombination rates. Gene annotations are shown as dark green lines.

Figure 4. Forest plots for common carotid IMT SNP associations

Plots show the study-specific association estimates (β) and 95% confidence intervals for the nine discovery and second stage studies, presented as bars. The scale is ln(cIMT). The association estimate and confidence interval for the meta-analysis combining discovery and second stage results is presented as a diamond. Blank spaces indicate occasions in which a particular study was not able to provide results for a given SNP.

Figure 5. Forest plots for plaque SNP associations

Plots show the study-specific association estimates (OR) and 95% confidence intervals for the nine discovery and second stage studies, presented as bars. The association estimate and confidence interval for the meta-analysis combining discovery and second stage results is presented as a diamond. Blank spaces indicate occasions in which a particular study was not able to provide results for a given SNP.