%0 Journal Article %J Invest Ophthalmol Vis Sci %D 2016 %T Assessing the Association of Mitochondrial Genetic Variation With Primary Open-Angle Glaucoma Using Gene-Set Analyses. %A Khawaja, Anthony P %A Cooke Bailey, Jessica N %A Kang, Jae Hee %A Allingham, R Rand %A Hauser, Michael A %A Brilliant, Murray %A Budenz, Donald L %A Christen, William G %A Fingert, John %A Gaasterland, Douglas %A Gaasterland, Terry %A Kraft, Peter %A Lee, Richard K %A Lichter, Paul R %A Liu, Yutao %A Medeiros, Felipe %A Moroi, Syoko E %A Richards, Julia E %A Realini, Tony %A Ritch, Robert %A Schuman, Joel S %A Scott, William K %A Singh, Kuldev %A Sit, Arthur J %A Vollrath, Douglas %A Wollstein, Gadi %A Zack, Donald J %A Zhang, Kang %A Pericak-Vance, Margaret %A Weinreb, Robert N %A Haines, Jonathan L %A Pasquale, Louis R %A Wiggs, Janey L %X

Purpose: Recent studies indicate that mitochondrial proteins may contribute to the pathogenesis of primary open-angle glaucoma (POAG). In this study, we examined the association between POAG and common variations in gene-encoding mitochondrial proteins. Methods: We examined genetic data from 3430 POAG cases and 3108 controls derived from the combination of the GLAUGEN and NEIGHBOR studies. We constructed biological-system coherent mitochondrial nuclear-encoded protein gene-sets by intersecting the MitoCarta database with the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. We examined the mitochondrial gene-sets for association with POAG and with normal-tension glaucoma (NTG) and high-tension glaucoma (HTG) subsets using Pathway Analysis by Randomization Incorporating Structure. Results: We identified 22 KEGG pathways with significant mitochondrial protein-encoding gene enrichment, belonging to six general biological classes. Among the pathway classes, mitochondrial lipid metabolism was associated with POAG overall (P = 0.013) and with NTG (P = 0.0006), and mitochondrial carbohydrate metabolism was associated with NTG (P = 0.030). Examining the individual KEGG pathway mitochondrial gene-sets, fatty acid elongation and synthesis and degradation of ketone bodies, both lipid metabolism pathways, were significantly associated with POAG (P = 0.005 and P = 0.002, respectively) and NTG (P = 0.0004 and P < 0.0001, respectively). Butanoate metabolism, a carbohydrate metabolism pathway, was significantly associated with POAG (P = 0.004), NTG (P = 0.001), and HTG (P = 0.010). Conclusions: We present an effective approach for assessing the contributions of mitochondrial genetic variation to open-angle glaucoma. Our findings support a role for mitochondria in POAG pathogenesis and specifically point to lipid and carbohydrate metabolism pathways as being important.

%B Invest Ophthalmol Vis Sci %V 57 %P 5046-5052 %8 2016 Sep 1 %G ENG %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/27661856?dopt=Abstract %R 10.1167/iovs.16-20017