Heart Rhythm
Volume 6, Issue 5 , Pages 634-641 , May 2009

Genome-wide association study of electrocardiographic conduction measures in an isolated founder population: Kosrae

  • J. Gustav Smith, MD

      Affiliations

    • Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge
    • Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts
    • Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts
  • ,
  • Jennifer K. Lowe, PhD

      Affiliations

    • Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge
    • Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts
  • ,
  • Sirisha Kovvali, BA

      Affiliations

    • Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge
  • ,
  • Julian B. Maller, BSc

      Affiliations

    • Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge
    • Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts
    • Department of Statistics, University of Oxford, Oxford, United Kingdom
  • ,
  • Jacqueline Salit, MS

      Affiliations

    • Laboratory of Molecular Genetics, Rockefeller University, New York, New York
  • ,
  • Mark J. Daly, PhD

      Affiliations

    • Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge
    • Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts
  • ,
  • Markus Stoffel, MD, PhD

      Affiliations

    • Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland
  • ,
  • David M. Altshuler, MD, PhD

      Affiliations

    • Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge
    • Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts
    • Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts
  • ,
  • Jeffrey M. Friedman, MD, PhD

      Affiliations

    • Laboratory of Molecular Genetics, Rockefeller University, New York, New York
  • ,
  • Jan L. Breslow, MD

      Affiliations

    • Laboratory of Biochemical Genetics and Metabolism, New York, New York
  • ,
  • Christopher Newton-Cheh, MD, MPH

      Affiliations

    • Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge
    • Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts
    • Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts
    • Corresponding Author InformationAddress reprint requests and correspondence: Christopher Newton-Cheh, M.D., M.P.H., Center for Human Genetic Research, Cardiovascular Research Center, Massachusetts General Hospital, 185 Cambridge Street, CPZN 5.242, Boston, Massachusetts 02114

Received 12 January 2009 ,Accepted 11 February 2009.

References 

  1. Platonov PG. Interatrial conduction in the mechanisms of atrial fibrillation: from anatomy to cardiac signals and new treatment modalities. Europace. 2007;9(Suppl 6):vi10–vi16
  2. Kashani A, Barold SS. Significance of QRS complex duration in patients with heart failure. J Am Coll Cardiol. 2005;46:2183–2192
  3. Newton-Cheh C, Guo CY, Wang TJ, et al. Genome-wide association study of electrocardiographic and heart rate variability traits: the Framingham Heart Study. BMC Med Genet. 2007;8(Suppl 1):S7
  4. Moller P, Heiberg A, Berg K. The atrioventricular conduction time—a heritable trait? III (Twin studies). Clin Genet. 1982;21:181–183
  5. Havlik RJ, Garrison RJ, Fabsitz R, et al. Variability of heart rate, P-R, QRS and Q-T durations in twins. J Electrocardiol. 1980;13:45–48
  6. Tan HL, Bink-Boelkens MT, Bezzina CR, et al. A sodium-channel mutation causes isolated cardiac conduction disease. Nature. 2001;409:1043–1047
  7. Schott JJ, Alshinawi C, Kyndt F, et al. Cardiac conduction defects associate with mutations in SCN5A. Net Genet. 1999;23:20–21
  8. Bezzina CR, Shimizu W, Yang P, et al. Common sodium channel promoter haplotype in Asian subjects underlies variability in cardiac conduction. Circulation. 2006;113:338–344
  9. Russell MW, Law I, Sholinsky P, et al. Heritability of ECG measurements in adult male twins. J Electrocardiol. 1998;30:S64–S68
  10. Gudbjartsson DF, Arnar DO, Helgadottir A, et al. Variants conferring risk of atrial fibrillation on chromosome 4q25. Nature. 2007;448:353–357
  11. Arking DE, Pfeufer A, Post W, et al. A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization. Nat Genet. 2006;38:644–651
  12. Bonnen PE, Pe'er I, Plenge RM, et al. Evaluating potential for whole-genome studies in Kosrae, an isolated population in Micronesia. Nat Genet. 2006;38:214–217
  13. Shmulewitz D, Auerbach SB, Lehner T, et al. Epidemiology and factor analysis of obesity, type II diabetes, hypertension, and dyslipidemia (syndrome X) on the Island of Kosrae, Federated States of Micronesia. Hum Hered. 2001;51:8–19
  14. Lowe JK, Maller JB, Pe'er I, et al. Genome-wide association studies in an isolated founder population from the Pacific Island of Kosrae. PLoS Gen. 2009;5:e1000365
  15. Purcell S, Neale B, Todd-Brown K, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81:559–575
  16. Rabbee N, Speed TP. A genotype calling algorithm for affymetrix SNP arrays. Bioinformatics. 2006;22:7–12
  17. Barrett JC, Fry B, Maller J, et al. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005;21:263–265
  18. Griggs LH, Chapman CJ, McHaffie DJ. Inheritance of atrioventricular conduction time in Tokelau Islanders. Clin Genet. 1986;29:56–61
  19. Darbar D, Kannankeril PJ, Donahue BS, et al. Cardiac sodium channel (SCN5A) variants associated with atrial fibrillation. Circulation. 2008;117:1927–1935
  20. Albert CM, Nam EG, Rimm EB, et al. Cardiac sodium channel gene variants and sudden cardiac death in women. Circulation. 2008;117:16–23
  21. Benson DW, Wang DW, Dyment M, et al. Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A). J Clin Invest. 2003;112:1019–1028
  22. Chen Q, Kirsch GE, Zhang D, et al. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature. 1998;392:293–296
  23. Olson TM, Michels VV, Ballew JD, et al. Sodium channel mutations and susceptibility to heart failure and atrial fibrillation. JAMA. 2005;293:447–454
  24. Smits JP, Koopmann TT, Wilders R, et al. A mutation in the human cardiac sodium channel (E161K) contributes to sick sinus syndrome, conduction disease and Brugada syndrome in two families. J Mol Cell Cardiol. 2005;38:969–981
  25. van Veen TA, Stein M, Royer A, et al. Impaired impulse propagation in Scn5a-knockout mice: combined contribution of excitability, connexin expression, and tissue architecture in relation to aging. Circulation. 2005;112:1927–1935
  26. Papadatos GA, Wallerstein PM, Head CE, et al. Slowed conduction and ventricular tachycardia after targeted disruption of the cardiac sodium channel gene Scn5a. Proc Nat Acad Sci U S A. 2002;99:6210–6215
  27. Zhang T, Yong SL, Tian XL, et al. Cardiac-specific overexpression of SCN5A gene leads to shorter P wave duration and PR interval in transgenic mice. Biochem Biophys Res Commun. 2007;355:444–450
  28. Royer A, van Veen TA, Le BS, et al. Mouse model of SCN5A-linked hereditary Lenegre's disease: age-related conduction slowing and myocardial fibrosis. Circulation. 2005;111:1738–1746
  29. Chen LY, Ballew JD, Herron KJ, et al. A common polymorphism in SCN5A is associated with lone atrial fibrillation. Clin Pharmacol Ther. 2007;81:35–41
  30. Splawski I, Timothy KW, Tateyama M, et al. Variant of SCN5A sodium channel implicated in risk of cardiac arrhythmia. Science. 2002;297:1333–1336
  31. Li GR, Lau CP, Shrier A. Heterogeneity of sodium current in atrial vs epicardial ventricular myocytes of adult guinea pig hearts. J Mol Cell Cardiol. 2002;34:1185–1194
  32. Lim JY, Park SJ, Hwang HY, et al. TGF-beta1 induces cardiac hypertrophic responses via PKC-dependent ATF-2 activation. J Mol Cell Cardiol. 2005;39:627–636
  33. Boogerd KJ, Wong LY, Christoffels VM, et al. Msx1 and Msx2 are functional interacting partners of T-box factors in the regulation of Connexin43. Cardiovasc Res. 2008;78:485–493
  34. Chen YH, Ishii M, Sucov HM, et al. Msx1 and Msx2 are required for endothelial-mesenchymal transformation of the atrioventricular cushions and patterning of the atrioventricular myocardium. BMC Dev Biol. 2008;8:75
  35. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007;447:661–678
  36. Pe'er I, Yelensky R, Altshuler D, et al. Estimation of the multiple testing burden for genomewide association studies of nearly all common variants. Genet Epidemiol. 2008;32:381–385
  37. Sehayek E, Yu HJ, von Bergmann K, et al. Phytosterolemia on the island of Kosrae: founder effect for a novel ABCG8 mutation results in high carrier rate and increased plasma plant sterol levels. J Lipid Res. 2004;45:1608–1613

 Dr. Newton-Cheh was supported by National Institutes of Health grant no. NIH K23-HL-080025, a Doris Duke Charitable Foundation Clinical Scientist Development Award, and a Burroughs Wellcome Fund Career Award for Medical Scientists. J.K. Lowe was supported by a Tosteson Post-Doctoral Fellowship for Basic Research from the Massachusetts Biomedical Research Corporation. Dr. Altshuler is a Burroughs Wellcome Fund Clinical Scholar in Translational Research and a Distinguished Clinical Scholar of the Doris Duke Charitable Foundation. The genome-wide association scan on Kosrae was supported by grants from the Starr Foundation and Howard Hughes Medical Institute.

PII: S1547-5271(09)00171-4

doi: 10.1016/j.hrthm.2009.02.022

Heart Rhythm
Volume 6, Issue 5 , Pages 634-641 , May 2009