Novel loci associated with increased risk of sudden cardiac death in the context of coronary artery disease

Abstract

Background: Recent genome-wide association studies (GWAS) have identified novel loci associated with sudden cardiac death (SCD). Despite this progress, identified DNA variants account for a relatively small portion of overall SCD risk, suggesting that additional loci contributing to SCD susceptibility await discovery. The objective of this study was to identify novel DNA variation associated with SCD in the context of coronary artery disease (CAD).

Methods and findings: Using the MetaboChip custom array we conducted a case-control association analysis of 119,117 SNPs in 948 SCD cases (with underlying CAD) from the Oregon Sudden Unexpected Death Study (Oregon-SUDS) and 3,050 controls with CAD from the Wellcome Trust Case-Control Consortium (WTCCC). Two newly identified loci were significantly associated with increased risk of SCD after correction for multiple comparisons at: rs6730157 in the RAB3GAP1 gene on chromosome 2 (P = 4.93×10(-12), OR = 1.60) and rs2077316 in the ZNF365 gene on chromosome 10 (P = 3.64×10(-8), OR = 2.41).

Conclusions: Our findings suggest that RAB3GAP1 and ZNF365 are relevant candidate genes for SCD and will contribute to the mechanistic understanding of SCD susceptibility.

Figure 1. Manhattan plot of associated findings.

Data is displayed as –log₁₀P values against chromosomal location for the 119,117 SNPs that were included in the statistical analysis. The dotted line represents the conservative significance threshold of P = 4.2×10⁻⁷. The two loci that showed an association at this level are plotted in red.

Figure 2. Regional association plots for the two associated SNPs with SCD.

Each SNP is plotted with respect to its chromosomal location (x-axis) and –log₁₀P-value (y-axis on the left). The spikes indicate the recombination rate (y-axis on the right) at that region of the chromosome.