Home LiteratureArticle Details
PMID: 21378987 Published · epublish English Journal Article Research Support, N.I.H., Extramural Validation Study

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

Nature genetics ·Vol. 43 ·No. 4 ·2011-03-06 ·Pages 316-20

Holm H, Gudbjartsson DF, Sulem P, Masson G, Helgadottir HT, Zanon C, Magnusson OT, Helgason A, Saemundsdottir J, Gylfason A, Stefansdottir H, Gretarsdottir S, Matthiasson SE, Thorgeirsson GM, Jonasdottir A, Sigurdsson A, Stefansson H, Werge T, Rafnar T, Kiemeney LA, Parvez B, Muhammad R, Roden DM, Darbar D, Thorleifsson G, Walters GB, Kong A, Thorsteinsdottir U, Arnar DO, Stefansson K

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.

MeSH Terms
Adult Aged Aged, 80 and over Cardiac Myosins/genetics Case-Control Studies Female Genetic Predisposition to Disease Genetic Variation Genome-Wide Association Study Heart Diseases/genetics Heart Rate/genetics Heterozygote Humans Iceland Male Middle Aged Mutation, Missense Myosin Heavy Chains/genetics Odds Ratio Oligonucleotide Array Sequence Analysis Penetrance Polymorphism, Single Nucleotide Sick Sinus Syndrome/genetics,physiopathology
Chemicals
MYH6 protein, human Cardiac Myosins Myosin Heavy Chains
Authors & Affiliations
30 authors, click to expand affiliations / ORCID
Holm Hilma
deCODE Genetics, Sturlugata 8, Reykjavik, Iceland. [email protected]
Gudbjartsson Daniel F
Sulem Patrick
Masson Gisli
Helgadottir Hafdis Th
Zanon Carlo
Magnusson Olafur Th
Helgason Agnar
Saemundsdottir Jona
Gylfason Arnaldur
Stefansdottir Hrafnhildur
Gretarsdottir Solveig
Matthiasson Stefan E
Thorgeirsson Gu Mundur
Jonasdottir Aslaug
Sigurdsson Asgeir
Stefansson Hreinn
Werge Thomas
Rafnar Thorunn
Kiemeney Lambertus A
Parvez Babar
Muhammad Raafia
Roden Dan M
Darbar Dawood
Thorleifsson Gudmar
Walters G Bragi
Kong Augustine
Thorsteinsdottir Unnur
Arnar David O
Stefansson Kari
References (30)
30 references, click to expand
  1. A map of human genome variation from population-scale sequencing.
    Nature. 2010 Oct 28;467(7319):1061-73 PMID: 20981092
  2. Detection of sharing by descent, long-range phasing and haplotype imputation.
    Nat Genet. 2008 Sep;40(9):1068-75 PMID: 19165921
  3. Genome-wide association analysis identifies multiple loci related to resting heart rate.
    Hum Mol Genet. 2010 Oct 1;19(19):3885-94 PMID: 20639392
  4. Patterns of expression in the developing myocardium: towards a morphologically integrated transcriptional model.
    Cardiovasc Res. 1998 Apr;38(1):25-53 PMID: 9683906
  5. Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel.
    N Engl J Med. 2006 Jan 12;354(2):151-7 PMID: 16407510
  6. A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes.
    Nat Genet. 1996 May;13(1):117-9 PMID: 8673089
  7. Alpha-cardiac myosin heavy chain (MYH6) mutations affecting myofibril formation are associated with congenital heart defects.
    Hum Mol Genet. 2010 Oct 15;19(20):4007-16 PMID: 20656787
  8. Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A).
    J Clin Invest. 2003 Oct;112(7):1019-28 PMID: 14523039
  9. Alpha-myosin heavy chain: a sarcomeric gene associated with dilated and hypertrophic phenotypes of cardiomyopathy.
    Circulation. 2005 Jul 5;112(1):54-9 PMID: 15998695
  10. Structural organization of the human cardiac alpha-myosin heavy chain gene (MYH6).
    Genomics. 1993 Dec;18(3):505-9 PMID: 8307559
  11. New insights into pacemaker activity: promoting understanding of sick sinus syndrome.
    Circulation. 2007 Apr 10;115(14):1921-32 PMID: 17420362
  12. Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death.
    Nature. 2003 Feb 6;421(6923):634-9 PMID: 12571597
  13. ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices) developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons.
    J Am Coll Cardiol. 2008 May 27;51(21):e1-62 PMID: 18498951
  14. Cardiac alpha- and beta-myosin heavy chain genes are organized in tandem.
    Proc Natl Acad Sci U S A. 1984 May;81(9):2626-30 PMID: 6585819
  15. Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia.
    Nat Genet. 2010 Aug;42(8):684-7 PMID: 20657596
  16. The sick sinus syndrome in atrial disease.
    JAMA. 1968 Oct 14;206(3):645-6 PMID: 5695590
  17. A family of microRNAs encoded by myosin genes governs myosin expression and muscle performance.
    Dev Cell. 2009 Nov;17(5):662-73 PMID: 19922871
  18. Prediction of deleterious human alleles.
    Hum Mol Genet. 2001 Mar 15;10(6):591-7 PMID: 11230178
  19. Myosin VI rewrites the rules for myosin motors.
    Cell. 2010 May 14;141(4):573-82 PMID: 20478251
  20. A haplotype map of the human genome.
    Nature. 2005 Oct 27;437(7063):1299-320 PMID: 16255080
  21. Myosin heavy chain isoform expression in the failing and nonfailing human heart.
    Circ Res. 2000 Mar 3;86(4):386-90 PMID: 10700442
  22. Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor.
    Hum Mol Genet. 2003 Feb 1;12(3):205-16 PMID: 12554675
  23. Multidrug resistance polypeptide 1 (MDR1, ABCB1) variant 3435C>T affects mRNA stability.
    Pharmacogenet Genomics. 2005 Oct;15(10):693-704 PMID: 16141795
  24. Cardiac pacing.
    N Engl J Med. 1996 Jan 11;334(2):89-97 PMID: 8531965
  25. Linkage disequilibrium analysis in young populations: pseudo-vitamin D-deficiency rickets and the founder effect in French Canadians.
    Am J Hum Genet. 1996 Sep;59(3):633-43 PMID: 8751865
  26. Estimating allele age.
    Annu Rev Genomics Hum Genet. 2000;1:225-49 PMID: 11701630
  27. A new multipoint method for genome-wide association studies by imputation of genotypes.
    Nat Genet. 2007 Jul;39(7):906-13 PMID: 17572673
  28. Contribution of sodium channel mutations to bradycardia and sinus node dysfunction in LQT3 families.
    Circ Res. 2003 May 16;92(9):976-83 PMID: 12676817
  29. Association between two mu-opioid receptor gene (OPRM1) haplotype blocks and drug or alcohol dependence.
    Hum Mol Genet. 2006 Mar 15;15(6):807-19 PMID: 16476706
  30. Several common variants modulate heart rate, PR interval and QRS duration.
    Nat Genet. 2010 Feb;42(2):117-22 PMID: 20062063
Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
DOI
10.1038/ng.781
Email
[email protected]
Published
2011-03-06
Epub
2011-00-06
Pages
316-20
Language
English
Region
United States
NLM ID
9216904
PMCID
PMC3066272
Subset
IM
Grants
NHLBI NIH HHS · R01 HL092217 · United States
NHLBI NIH HHS · U19 HL065962 · United States
NHLBI NIH HHS · HL092217 · United States
NHLBI NIH HHS · U19HL065962 · United States
NHLBI NIH HHS · R01 HL092217-03 · United States
NHLBI NIH HHS · U19 HL065962-10 · United States
Corrections
CommentIn
PMID: 21445070
External Links
PubMed source DOI: 10.1038/ng.781 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2