TY - JOUR
T1 - Common variants within oxidative phosphorylation genes influence risk of ischemic stroke and intracerebral hemorrhage
AU - Anderson, Christopher D.
AU - Biffi, Alessandro
AU - Nalls, Michael A.
AU - Devan, William J.
AU - Schwab, Kristin
AU - Ayres, Alison M.
AU - Valant, Valerie
AU - Ross, Owen A.
AU - Rost, Natalia S.
AU - Saxena, Richa
AU - Viswanathan, Anand
AU - Worrall, Bradford B.
AU - Brott, Thomas G.
AU - Goldstein, Joshua N.
AU - Brown, Devin
AU - Broderick, Joseph P.
AU - Norrving, Bo
AU - Greenberg, Steven M.
AU - Silliman, Scott L.
AU - Hansen, Björn M.
AU - Tirschwell, David L.
AU - Lindgren, Arne
AU - Slowik, Agnieszka
AU - Schmidt, Reinhold
AU - Selim, Magdy
AU - Roquer, Jaume
AU - Montaner, Joan
AU - Singleton, Andrew B.
AU - Kidwell, Chelsea S.
AU - Woo, Daniel
AU - Furie, Karen L.
AU - Meschia, James F.
AU - Rosand, Jonathan
PY - 2013/3
Y1 - 2013/3
N2 - Background and Purpose-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.
AB - Background and Purpose-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.
KW - Genes
KW - Mitochondria
KW - OXPHOS
KW - Stroke
UR - http://www.scopus.com/inward/record.url?scp=84876292195&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84876292195&partnerID=8YFLogxK
U2 - 10.1161/STROKEAHA.112.672089
DO - 10.1161/STROKEAHA.112.672089
M3 - Article
C2 - 23362085
AN - SCOPUS:84876292195
SN - 0039-2499
VL - 44
SP - 612
EP - 619
JO - Stroke
JF - Stroke
IS - 3
ER -