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. published online 17 February 2009.

Background

Cardiac conduction, as assessed by electrocardiographic PR interval and QRS duration, is an important electrophysiological trait and a determinant of arrhythmia risk.

Objective

We sought to identify common genetic determinants of these measures.

Methods

We examined 1604 individuals from the island of Kosrae, Federated States of Micronesia, an isolated founder population. We adjusted for covariates and estimated the heritability of quantitative electrocardiographic QRS duration and PR interval and, secondarily, its subcomponents, P-wave duration and PR segment. Finally, we performed a genome-wide association study (GWAS) in a subset of 1262 individuals genotyped using the Affymetrix GeneChip Human Mapping 500K microarray.

Results

The heritability of PR interval was 34% (standard error [SE] 5%, P = 4 × 10−18); of PR segment, 31% (SE 6%, P = 3.2 × 10−13); and of P-wave duration, 17% (SE 5%, P = 5.8 × 10−6), but the heritablility of QRS duration was only 3% (SE 4%, P = .20). Hence, GWAS was performed only for the PR interval and its subcomponents. A total of 338,049 single nucleotide polymorphisms (SNPs) passed quality filters. For the PR interval, the most significantly associated SNPs were located in and downstream of the alpha-subunit of the cardiac voltage-gated sodium channel gene SCN5A, with a 4.8 ms (SE 1.0) or 0.23 standard deviation increase in adjusted PR interval for each minor allele copy of rs7638909 (P = 1.6 × 10−6, minor allele frequency 0.40). These SNPs were also associated with P-wave duration (P = 1.5 × 10−4) and PR segment (P = .01) but not with QRS duration (P ≥.22).

Conclusions

The PR interval and its subcomponents showed substantial heritability in a South Pacific islander population and were associated with common genetic variation in SCN5A.

Keywords: Conduction, Electrocardiography, Electrophysiology, Genetics, Ion channels

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 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

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