Common mitochondrial sequence variants in ischemic stroke

Authors

  • Christopher D. Anderson MD,

    1. Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA
    2. Department of Neurology, Massachusetts General Hospital, Boston MA
    3. Program in Medical and Population Genetics, Broad Institute, Cambridge, MA
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    • C.D.A. and A.B. contributed equally to the present study.

  • Alessandro Biffi MD,

    1. Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA
    2. Department of Neurology, Massachusetts General Hospital, Boston MA
    3. Program in Medical and Population Genetics, Broad Institute, Cambridge, MA
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    • C.D.A. and A.B. contributed equally to the present study.

  • Rosanna Rahman PhD,

    1. Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA
    2. Department of Neurology, Massachusetts General Hospital, Boston MA
    3. Program in Medical and Population Genetics, Broad Institute, Cambridge, MA
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  • Owen A. Ross PhD,

    1. Department of Neurology, Mayo Clinic, Jacksonville, FL
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  • Jeremiasz M. Jagiella MD, PhD,

    1. Department of Neurology, Jagiellonian University Medical College, Krakow, Poland
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  • Brett Kissela MD, MS,

    1. Department of Neurology, University of Cincinnati College of Medicine, Cincinnati, OH
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  • John W. Cole MD,

    1. Department of Neurology, University of Maryland, Baltimore, MD
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  • Lynelle Cortellini MSc,

    1. Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA
    2. Department of Neurology, Massachusetts General Hospital, Boston MA
    3. Program in Medical and Population Genetics, Broad Institute, Cambridge, MA
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  • Natalia S. Rost MD,

    1. Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA
    2. Department of Neurology, Massachusetts General Hospital, Boston MA
    3. Program in Medical and Population Genetics, Broad Institute, Cambridge, MA
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  • Yu-Ching Cheng PhD,

    1. Department of Neurology, University of Maryland, Baltimore, MD
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  • Steven M. Greenberg MD, PhD,

    1. Department of Neurology, Massachusetts General Hospital, Boston MA
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  • Paul I.W. de Bakker PhD,

    1. Program in Medical and Population Genetics, Broad Institute, Cambridge, MA
    2. Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
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  • Robert D. Brown Jr MD,

    1. Department of Neurology, Mayo Clinic, Rochester, MN
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  • Thomas G. Brott MD,

    1. Department of Neurology, Mayo Clinic, Jacksonville, FL
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  • Braxton D. Mitchell MD,

    1. Department of Neurology, University of Maryland, Baltimore, MD
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  • Joseph P. Broderick MD,

    1. Department of Neurology, University of Cincinnati College of Medicine, Cincinnati, OH
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  • Bradford B. Worrall MD,

    1. Department of Neurology and Public Health Sciences, University of Virginia Health System, Charlottesville, VA
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  • Karen L. Furie MD, MPH,

    1. Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA
    2. Department of Neurology, Massachusetts General Hospital, Boston MA
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  • Steven J. Kittner MD,

    1. Department of Neurology, University of Maryland, Baltimore, MD
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  • Daniel Woo MD, MSc,

    1. Department of Neurology, University of Cincinnati College of Medicine, Cincinnati, OH
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  • Agnieszka Slowik MD, PhD,

    1. Department of Neurology, Jagiellonian University Medical College, Krakow, Poland
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  • James F. Meschia MD,

    1. Department of Neurology, Mayo Clinic, Jacksonville, FL
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  • Richa Saxena PhD,

    1. Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA
    2. Program in Medical and Population Genetics, Broad Institute, Cambridge, MA
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  • Jonathan Rosand MD, MSc,

    Corresponding author
    1. Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA
    2. Department of Neurology, Massachusetts General Hospital, Boston MA
    3. Program in Medical and Population Genetics, Broad Institute, Cambridge, MA
    • Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge Street, CPZN-6818, Boston, MA 02114
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  • on behalf of the International Stroke Genetics Consortium


  • Potential conflict of interest:

Abstract

Objective

Rare mitochondrial mutations cause neurologic disease, including ischemic stroke and MRI white matter changes. We investigated whether common mitochondrial genetic variants influence risk of sporadic ischemic stroke and, in patients with stroke, the volume of white matter hyperintensity (WMHV).

Methods

In this multicenter, mitochondrial genome-wide association study (GWAS), 2284 ischemic stroke cases and 1728 controls from the International Stroke Genetics Consortium were genotyped for 64 mitochondrial single nucleotide polymorphisms (SNPs). Imputation resulted in 144 SNPs, which were tested in each cohort and in meta-analysis for ischemic stroke association. A genetic score of all mitochondrial variants was also tested in association with ischemic stroke.

Results

No individual SNP reached adjusted significance in meta-analysis. A genetic score comprised of the summation of contributions from individual variants across the mitochondrial genome showed association with ischemic stroke in meta-analysis (odds ratio [OR] = 1.13, p < 0.0001) with minimal heterogeneity (I2 = 0.00). This ischemic stroke score was robust to permutation, and was also associated with WMHV in 792 nested case individuals with ischemic stroke (p = 0.037).

Interpretation

In this mitochondrial GWAS of ischemic stroke, a genetic score comprised of the sum of all common variants in the mitochondrial genome showed association with ischemic stroke. In an independent analysis of a related trait, this same score correlated with WMHV in stroke cases. Despite this aggregate association, no individual variant reached significance. Substantially larger studies will be required to identify precise sequence variants influencing cerebrovascular disease.ANN NEUROL 2010;00:000–000

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