Common variants within oxidative phosphorylation genes influence risk of ischemic stroke and intracerebral hemorrhage.
OBJECTIVE
Previous studies demonstrated association between mitochondrial DNA variants and ischemic stroke (IS). We investigated whether variants within a larger set of oxidative phosphorylation (OXPHOS) genes encoded by both autosomal and mitochondrial DNA were associated with risk of IS and, based on our results, extended our investigation to intracerebral hemorrhage (ICH).


METHODS
This association study used a discovery cohort of 1643 individuals, a validation cohort of 2432 individuals for IS, and an extension cohort of 1476 individuals for ICH. Gene-set enrichment analysis was performed on all structural OXPHOS genes, as well as genes contributing to individual respiratory complexes. Gene-sets passing gene-set enrichment analysis were tested by constructing genetic scores using common variants residing within each gene. Associations between each variant and IS that emerged in the discovery cohort were examined in validation and extension cohorts.


RESULTS
IS was associated with genetic risk scores in OXPHOS as a whole (odds ratio [OR], 1.17; P=0.008) and complex I (OR, 1.06; P=0.050). Among IS subtypes, small vessel stroke showed association with OXPHOS (OR, 1.16; P=0.007), complex I (OR, 1.13; P=0.027), and complex IV (OR, 1.14; P=0.018). To further explore this small vessel association, we extended our analysis to ICH, revealing association between deep hemispheric ICH and complex IV (OR, 1.08; P=0.008).


CONCLUSIONS
This pathway analysis demonstrates association between common genetic variants within OXPHOS genes and stroke. The associations for small vessel stroke and deep ICH suggest that genetic variation in OXPHOS influences small vessel pathobiology. Further studies are needed to identify culprit genetic variants and assess their functional consequences.
Massachusetts General Hospital, Boston, MA 02114, USA. cdanderson@partners.org
Christopher D
CD
Anderson
Alessandro
A
Biffi
Michael A
MA
Nalls
William J
WJ
Devan
Kristin
K
Schwab
Alison M
AM
Ayres
Valerie
V
Valant
Owen A
OA
Ross
Natalia S
NS
Rost
Richa
R
Saxena
Anand
A
Viswanathan
Bradford B
BB
Worrall
Thomas G
TG
Brott
Joshua N
JN
Goldstein
Devin
D
Brown
Joseph P
JP
Broderick
Bo
B
Norrving
Steven M
SM
Greenberg
Scott L
SL
Silliman
Björn M
BM
Hansen
David L
DL
Tirschwell
Arne
A
Lindgren
Agnieszka
A
Slowik
Reinhold
R
Schmidt
Magdy
M
Selim
Jaume
J
Roquer
Joan
J
Montaner
Andrew B
AB
Singleton
Chelsea S
CS
Kidwell
Daniel
D
Woo
Karen L
KL
Furie
James F
JF
Meschia
Jonathan
J
Rosand
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002543:Cerebral Hemorrhage / Q000453:epidemiology / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D005796:Genes / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010085:Oxidative Phosphorylation; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D020521:Stroke / Q000453:epidemiology / Q000235:genetics*