Identification of a sudden cardiac death susceptibility locus at 2q24.2 through genome-wide association in European ancestry individuals

Abstract

Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000-300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8×10(-10)). The risk allele, while ancestral, has a frequency of ~1.4%, suggesting strong negative selection and increases risk for SCD by 1.92-fold per allele (95% CI 1.57-2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006).

Figure 1. Regional association plot for rs4655058.

Each SNP is plotted with respect to its chromosomal location (x-axis) and P-value (y-axis on the left). The tall blue spikes indicate the recombination rate (y-axis on the right) at that region of the chromosome. The index SNP is denoted by the larger diamond, for both the GWAS (red) and combined GWAS and validation results (blue). The dotted black line denotes genome-wide significance (P<5×10⁻⁸). Shading of additional SNPs indicates degree of linkage disequilibrium with the index SNP (red: r²≥0.8, orange: 0.5≤r²<0.8, grey: 0.2≤r²<0.5, white: r²<0.2).