title: Common mitochondrial sequence variants in ischemic stroke.
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 (I(2) = 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, 02114, USA.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Anderson
authors.forename: Alessandro
authors.initials: A
authors.lastname: Biffi
authors.forename: Rosanna
authors.initials: R
authors.lastname: Rahman
authors.forename: Owen A
authors.initials: OA
authors.lastname: Ross
authors.forename: Jeremiasz M
authors.initials: JM
authors.lastname: Jagiella
authors.forename: Brett
authors.initials: B
authors.lastname: Kissela
authors.forename: John W
authors.initials: JW
authors.lastname: Cole
authors.forename: Lynelle
authors.initials: L
authors.lastname: Cortellini
authors.forename: Natalia S
authors.initials: NS
authors.lastname: Rost
authors.forename: Yu-Ching
authors.initials: YC
authors.lastname: Cheng
authors.forename: Steven M
authors.initials: SM
authors.lastname: Greenberg
authors.forename: Paul I W
authors.initials: PI
authors.lastname: de Bakker
authors.forename: Robert D
authors.initials: RD
authors.lastname: Brown
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Brott
authors.forename: Braxton D
authors.initials: BD
authors.lastname: Mitchell
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Broderick
authors.forename: Bradford B
authors.initials: BB
authors.lastname: Worrall
authors.forename: Karen L
authors.initials: KL
authors.lastname: Furie
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Kittner
authors.forename: Daniel
authors.initials: D
authors.lastname: Woo
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Slowik
authors.forename: James F
authors.initials: JF
authors.lastname: Meschia
authors.forename: Richa
authors.initials: R
authors.lastname: Saxena
authors.forename: Jonathan
authors.initials: J
authors.lastname: Rosand
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002545:Brain Ischemia / Q000235:genetics*; D005260:Female; D050259:Genes, Mitochondrial / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D020521:Stroke / Q000235:genetics*; D044465:White People