Editors' ChoiceHuman Genomics

When the Heart Forgets to Beat

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Science Translational Medicine  30 Mar 2011:
Vol. 3, Issue 76, pp. 76ec42
DOI: 10.1126/scitranslmed.3002424

The heart’s sinus node keeps it thumping regularly and rhythmically, day after day. Unfortunately, as we age, the sinus node can dysfunction. Sinus node malfunction, termed sick sinus syndrome (SSS), accounts for over half of the 150,000 external pacemakers annually implanted in the United States. To make matters worse, currently no accurate method exists to predict who might develop this dangerous condition. Holm et al. have now uncovered genetic underpinnings of common forms of SSS that may help to fill this glaring void.

The authors performed a genome-wide association study (GWAS) in which 792 Icelandic individuals with SSS and 37,592 controls were directly genotyped for over 7 million single nucleotide polymorphisms (SNPs). A strong association signal (P = 1.3 × 10–13) was found at chromosome 14q11; this was further explored by the whole-genome sequencing of an additional 87 cases and controls. The authors then used the whole-genome–sequencing data to generate a total of 11 million SNPs that were then tested in a second-stage GWAS. Interestingly, the same chromosomal region on 14q11 was again found to be most significantly associated with SSS.

The extensive SNP analysis pointed to a culprit: a missense mutation in MYH6, which encodes the alpha subunit of the cardiac myosin muscle protein. This rare variant, resulting in an arginine–for-tryptophan substitution (c.2161C>T) in exon 18 and present in 0.38% of Icelandic individuals, conferred a striking 12-fold increase in risk for SSS in two independent cohorts. In another cohort with documented fainting episodes (syncope), 50% of individuals carrying the at-risk c.2161C>T mutation were diagnosed with SSS, versus only 19% of noncarriers. In the future, genetic analysis of SSS markers will help clinicians cinch the cause of syncope, which otherwise involves an extensive, challenging, and costly work-up.

Although the mechanism by which MYH6 sequence variants alter cardiac conduction and rhythmicity remains unknown, the current study illustrates the power of combining GWAS with whole-genome sequencing to uncover the “missing” heritability of common disorders. Given the rapidly declining cost of DNA sequencing, the future portends discovery of additional rare variants that cause the heart to forget to beat.

H. Holm et al., A rare variant in MYH6 is associated with high risk of sick sinus syndrome. Nat. Genet. 6 March 2011 (10.1038/ng.781). [Abstract]

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