Common mitochondrial sequence variants in ischemic stroke.
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.
Anderson
Christopher D
CD
Center for Human Genetic Research, Massachusetts General Hospital, Boston, 02114, USA.
Biffi
Alessandro
A
Rahman
Rosanna
R
Ross
Owen A
OA
Jagiella
Jeremiasz M
JM
Kissela
Brett
B
Cole
John W
JW
Cortellini
Lynelle
L
Rost
Natalia S
NS
Cheng
Yu-Ching
YC
Greenberg
Steven M
SM
de Bakker
Paul I W
PI
Brown
Robert D
RD
Brott
Thomas G
TG
Mitchell
Braxton D
BD
Broderick
Joseph P
JP
Worrall
Bradford B
BB
Furie
Karen L
KL
Kittner
Steven J
SJ
Woo
Daniel
D
Slowik
Agnieszka
A
Meschia
James F
JF
Saxena
Richa
R
Rosand
Jonathan
J
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