Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death

Abstract

Brugada syndrome is a rare cardiac arrhythmia disorder, causally related to SCN5A mutations in around 20% of cases. Through a genome-wide association study of 312 individuals with Brugada syndrome and 1,115 controls, we detected 2 significant association signals at the SCN10A locus (rs10428132) and near the HEY2 gene (rs9388451). Independent replication confirmed both signals (meta-analyses: rs10428132, P = 1.0 × 10(-68); rs9388451, P = 5.1 × 10(-17)) and identified one additional signal in SCN5A (at 3p21; rs11708996, P = 1.0 × 10(-14)). The cumulative effect of the three loci on disease susceptibility was unexpectedly large (Ptrend = 6.1 × 10(-81)). The association signals at SCN5A-SCN10A demonstrate that genetic polymorphisms modulating cardiac conduction can also influence susceptibility to cardiac arrhythmia. The implication of association with HEY2, supported by new evidence that Hey2 regulates cardiac electrical activity, shows that Brugada syndrome may originate from altered transcriptional programming during cardiac development. Altogether, our findings indicate that common genetic variation can have a strong impact on the predisposition to rare diseases.

Figure 1

Genome-wide association analysis identifies two susceptibility loci for Brugada syndrome. (a) Manhattan plot showing the association of SNPs with Brugada syndrome in a GWAS of 312 cases and 1,115 controls. The red horizontal line marks the threshold for genome-wide significance (P = 5 × 10⁻⁸). Two loci reached genome-wide significance on chromosomes 3 and 6. (b) Association plots for 3q22 (left) and 6q22 (right). Each SNP is plotted with respect to its chromosomal location (x axis) and its association P value (left y axis). SNPs are colored according to their degree of LD (r²) with the leading variant represented by a purple diamond and labeled. The tall blue spikes indicate the recombination rate (right y axis) in that region of the chromosome. Coordinates are given according to NCBI Build 37.

Figure 2

Cumulative effect of alleles at the three associated loci on susceptibility to Brugada syndrome. (a) Distribution of risk alleles among individuals with Brugada syndrome (white bars) and among control individuals (black bars) from Europe (top) and Japan (bottom). (b) ORs calculated according to the number of risk alleles carried. A meta-analysis was performed as described in the Online Methods, using individuals carrying no or one risk allele as the reference. Each black bar represents the log(OR) value (horizontal bar) and the 95% confidence interval (on the log scale; vertical bar).

Figure 3

Increased conduction velocity and sodium channel availability in the RVOT of adult Hey2^+/− mice. (a) Representative optical activation maps from isolated wild-type (WT; n = 12) and Hey2^+/− (n = 11) hearts stimulated at the RVOT at a basic cycle length of 120 ms (scale bars, 1 mm). Arrows indicate conduction along the RVOT epicardium through the connection of similar isochrones. Isochrones (0.5-ms intervals) in the RVOT of Hey2^+/− hearts are less crowded compared to wild-type isochromes, indicating faster conduction in the RVOT of Hey2^+/− hearts (as indicated by increased arrow length). (b) On average, conduction velocity in the RVOT of Hey2^+/− hearts was significantly increased compared to that in wild-type hears (*P < 0.05; Student’s t test). Error bars, s.e.m. (c) Representative action potentials measured in adult wild-type (WT; n = 7) and Hey2^+/− (n = 11) cardiomyocytes isolated from RVOT. (d) Average action potential characteristics measured at 4 Hz. RVOT cardiomyocytes from Hey2^+/− mice showed a significant increase in maximal upstroke velocity (dV/dT_max, a measure of sodium channel availability and a determinant of conduction velocity) and action potential amplitude (APA), indicating increased sodium channel availability (*P < 0.05; **P < 0.01; Student’s t test). Resting membrane potential (RMP), action potential duration at 20% and 50% repolarization (APD₂₀ and APD₅₀, respectively) were not significantly different in wild-type and Hey2^+/− mice; action potential duration at 90% repolarization (APD₉₀) was significantly increased in RVOT cardiomyocytes from Hey2^+/− mice. Results are expressed as mean ± s.e.m.