Assessing the Association of Mitochondrial Genetic Variation With Primary Open-Angle Glaucoma Using Gene-Set Analyses.


Journal Article

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.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.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).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.

Full Text

Duke Authors

Cited Authors

  • Khawaja, AP; Cooke Bailey, JN; Kang, JH; Allingham, RR; Hauser, MA; Brilliant, M; Budenz, DL; Christen, WG; Fingert, J; Gaasterland, D; Gaasterland, T; Kraft, P; Lee, RK; Lichter, PR; Liu, Y; Medeiros, F; Moroi, SE; Richards, JE; Realini, T; Ritch, R; Schuman, JS; Scott, WK; Singh, K; Sit, AJ; Vollrath, D; Wollstein, G; Zack, DJ; Zhang, K; Pericak-Vance, M; Weinreb, RN; Haines, JL; Pasquale, LR; Wiggs, JL

Published Date

  • September 2016

Published In

Volume / Issue

  • 57 / 11

Start / End Page

  • 5046 - 5052

PubMed ID

  • 27661856

Pubmed Central ID

  • 27661856

Electronic International Standard Serial Number (EISSN)

  • 1552-5783

International Standard Serial Number (ISSN)

  • 0146-0404

Digital Object Identifier (DOI)

  • 10.1167/iovs.16-20017


  • eng