Assessing the association of mitochondrial genetic variation with primary open-angle glaucoma using gene-set analyses

Anthony P. Khawaja, Jessica N. Cooke Bailey, Jae Hee Kang, R. Rand Allingham, Michael A. Hauser, Murray Brilliant, Donald L. Budenz, William G. Christen, John Fingert, Douglas Gaasterland, Terry Gaasterland, Peter Kraft, Richard K. Lee, Paul R. Lichter, Yutao Liu, Felipe Medeiros, Syoko E. Moroi, Julia E. Richards, Tony Realini, Robert RitchJoel S. Schuman, William K. Scott, Kuldev Singh, Arthur J. Sit, Douglas Vollrath, Gadi Wollstein, Donald J. Zack, Kang Zhang, Margaret Pericak-Vance, Robert N. Weinreb, Jonathan L. Haines, Louis R. Pasquale, Janey L. Wiggs

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)5046-5052
Number of pages7
JournalInvestigative Ophthalmology and Visual Science
Issue number11
StatePublished - Sep 2016


  • Genetics
  • Glaucoma
  • Mitochondria

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience


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