A rare variant in MYH6 is associated with high risk of sick sinus syndrome

Abstract

Through complementary application of SNP genotyping, whole-genome sequencing and imputation in 38,384 Icelanders, we have discovered a previously unidentified sick sinus syndrome susceptibility gene, MYH6, encoding the alpha heavy chain subunit of cardiac myosin. A missense variant in this gene, c.2161C>T, results in the conceptual amino acid substitution p.Arg721Trp, has an allelic frequency of 0.38% in Icelanders and associates with sick sinus syndrome with an odds ratio = 12.53 and P = 1.5 × 10⁻²⁹. We show that the lifetime risk of being diagnosed with sick sinus syndrome is around 6% for non-carriers of c.2161C>T but is approximately 50% for carriers of the c.2161C>T variant.

Figure 1

Study design and outcomes. The white boxes describe study actions performed. The blue boxes describe results from preceding actions. SSS, sick sinus syndrome.

Figure 2

An overview of the region around c.2161C>T. The black circles show −log₁₀ P for association with sick sinus syndrome for imputed SNPs based on whole-genome sequencing as a function of their build 36 coordinates. The orange crosses show results conditional on the effect of c.2161C>T. Neighboring genes are shown in blue. Recombination rates are reported in cM/Mb.

Figure 3

Penetrance of sick sinus syndrome among carriers and non-carriers of c.2161C>T. The red crosses represent observed penetrance of sick sinus syndrome for 10-year birth cohorts among heterozygous carriers of c.2161C>T. The red line represents the fit of the logistic model to the c.2161C>T carrier data. The blue line and crosses represent the same information for non-carriers of c.2161C>T. SSS, sick sinus syndrome.