Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease

Abstract

We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 individuals with CAD (cases) and 64,762 controls of European descent followed by genotyping of top association signals in 56,682 additional individuals. This analysis identified 13 loci newly associated with CAD at P < 5 × 10⁻⁸ and confirmed the association of 10 of 12 previously reported CAD loci. The 13 new loci showed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6% to 17% increase in the risk of CAD per allele. Notably, only three of the new loci showed significant association with traditional CAD risk factors and the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the new CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits.

Figure 1. Graphical summary (Manhattan plot) of genome-wide association results

The x-axis represents the genome in physical order; the y-axis shows -log₁₀ P values for all SNPs. Data from the discovery phase are shown in circles and data from the combined discovery and replication phases in stars. Genes at the significant loci are listed above the signals. Known loci are shown in red and novel loci are shown in blue.

Figure 2. Example of overlapping association signals for multiple traits at ABO gene region on chromosome 9q34

In the upper panel the association signal for coronary disease at the ABO gene region in CARDIoGRAM and the positions and rs-numbers of SNPs in this region are shown. The size of boxes illustrates the number of individuals available for this respective SNP. In the lower panel all SNPs with P-values at genome-wide significance level of P<5×10⁻⁸ based on the NHGRI GWA study catalogue (http://www.genome.gov/gwastudies/; accessed on June 28^th 2010) for all diseases and traits are shown. The degree of linkage disequilibrium (r²) between the lead SNPs for coronary disease and the other traits is reflected by the colour of the squares (upper panel) and the small bars (lower panel) (dark red (high LD) > faint red (low LD)). SI/CH = sitosterol normalized to cholesterol; CA/CH = campesterol normalized to cholesterol; ALP = alkaline phosphatase; ACE = angiotensin converting enzyme; FVIII = coagulation factor VIII; vWF = von Willebrand Factor.