Common mitochondrial sequence variants in ischemic stroke

Christopher D. Anderson, Alessandro Biffi, Rosanna Rahman, Owen A Ross, Jeremiasz M. Jagiella, Brett Kissela, John W. Cole, Lynelle Cortellini, Natalia S. Rost, Yu Ching Cheng, Steven M. Greenberg, Paul I W De Bakker, Robert D Jr. Brown, Thomas G Brott, Braxton D. Mitchell, Joseph P. Broderick, Bradford B. Worrall, Karen L. Furie, Steven J. Kittner, Daniel WooAgnieszka Slowik, James F Meschia, Richa Saxena, Jonathan Rosand

Research output: Contribution to journalArticle

29 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)471-480
Number of pages10
JournalAnnals of Neurology
Volume69
Issue number3
DOIs
StatePublished - Mar 2011

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Stroke
Mitochondrial Genome
Single Nucleotide Polymorphism
Meta-Analysis
Genome-Wide Association Study
Cerebrovascular Disorders
Nervous System Diseases
Stroke Volume
Odds Ratio
Mutation

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Anderson, C. D., Biffi, A., Rahman, R., Ross, O. A., Jagiella, J. M., Kissela, B., ... Rosand, J. (2011). Common mitochondrial sequence variants in ischemic stroke. Annals of Neurology, 69(3), 471-480. https://doi.org/10.1002/ana.22108

Common mitochondrial sequence variants in ischemic stroke. / Anderson, Christopher D.; Biffi, Alessandro; Rahman, Rosanna; Ross, Owen A; Jagiella, Jeremiasz M.; Kissela, Brett; Cole, John W.; Cortellini, Lynelle; Rost, Natalia S.; Cheng, Yu Ching; Greenberg, Steven M.; De Bakker, Paul I W; Brown, Robert D Jr.; Brott, Thomas G; Mitchell, Braxton D.; Broderick, Joseph P.; Worrall, Bradford B.; Furie, Karen L.; Kittner, Steven J.; Woo, Daniel; Slowik, Agnieszka; Meschia, James F; Saxena, Richa; Rosand, Jonathan.

In: Annals of Neurology, Vol. 69, No. 3, 03.2011, p. 471-480.

Research output: Contribution to journalArticle

Anderson, CD, Biffi, A, Rahman, R, Ross, OA, Jagiella, JM, Kissela, B, Cole, JW, Cortellini, L, Rost, NS, Cheng, YC, Greenberg, SM, De Bakker, PIW, Brown, RDJ, Brott, TG, Mitchell, BD, Broderick, JP, Worrall, BB, Furie, KL, Kittner, SJ, Woo, D, Slowik, A, Meschia, JF, Saxena, R & Rosand, J 2011, 'Common mitochondrial sequence variants in ischemic stroke', Annals of Neurology, vol. 69, no. 3, pp. 471-480. https://doi.org/10.1002/ana.22108
Anderson CD, Biffi A, Rahman R, Ross OA, Jagiella JM, Kissela B et al. Common mitochondrial sequence variants in ischemic stroke. Annals of Neurology. 2011 Mar;69(3):471-480. https://doi.org/10.1002/ana.22108
Anderson, Christopher D. ; Biffi, Alessandro ; Rahman, Rosanna ; Ross, Owen A ; Jagiella, Jeremiasz M. ; Kissela, Brett ; Cole, John W. ; Cortellini, Lynelle ; Rost, Natalia S. ; Cheng, Yu Ching ; Greenberg, Steven M. ; De Bakker, Paul I W ; Brown, Robert D Jr. ; Brott, Thomas G ; Mitchell, Braxton D. ; Broderick, Joseph P. ; Worrall, Bradford B. ; Furie, Karen L. ; Kittner, Steven J. ; Woo, Daniel ; Slowik, Agnieszka ; Meschia, James F ; Saxena, Richa ; Rosand, Jonathan. / Common mitochondrial sequence variants in ischemic stroke. In: Annals of Neurology. 2011 ; Vol. 69, No. 3. pp. 471-480.
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AU - Furie, Karen L.

AU - Kittner, Steven J.

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AU - Slowik, Agnieszka

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N2 - 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.

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