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

Author(s): Khawaja AP(1), Cooke Bailey JN(2), Kang JH(3), Allingham RR(4), Hauser MA(5), Brilliant M(6), Budenz DL(7), Christen WG(8), Fingert J(9), Gaasterland D(10), Gaasterland T(11), Kraft P(12), Lee RK(13), Lichter PR(14), Liu Y(15), Medeiros F(16), Moroi SE(14), Richards JE(17), Realini T(18), Ritch R(19), Schuman JS(20), Scott WK(21), Singh K(22), Sit AJ(23), Vollrath D(24), Wollstein G(25), Zack DJ(26), Zhang K(16), Pericak-Vance M(21), Weinreb RN(16), Haines JL(2), Pasquale LR(27), Wiggs JL(28)

1 National Institute for Health Research (NIHR) Biomedical Research Centre, Moorfields Eye Hospital National Health Service (NHS) Foundation Trust, and University College London (UCL) Institute of Ophthalmology, London, United Kingdom.
2 Department of Epidemiology and Biostatistics, Institute for Computational Biology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States.
3 Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States.
4 Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina, United States.
5 Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina, United States 5Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States.
6 Marshfield Clinic Research Foundation, Marshfield, Wisconsin, United States.
7 Department of Ophthalmology, University of North Carolina, Chapel Hill, North Carolina, United States.
8 Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States.
9 Department of Ophthalmology, University of Iowa, College of Medicine, Iowa City, Iowa, United States 10Stephen A. Wynn Institute for Vision Research, Iowa City, Iowa, United States.
10 The Emmes Corporation, Rockville, Maryland, United States.
11 Scripps Genome Center, University of California at San Diego, San Diego, California, United States.
12 Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, United States 14Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, Massachusetts, United States.
13 Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, United States.
14 Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States.
15 Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, Georgia, United States 18James and Jean Culver Vision Discovery Institute, Medical College of Georgia, Augusta University, Augusta, Georgia, United States.
16 Hamilton Glaucoma Center, Shiley Eye Institute, University of California, San Diego, San Diego, California, United States.
17 Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States 20Department of Epidemiology, University of Michigan, Ann Arbor, Michigan, United States.
18 Department of Ophthalmology, West Virginia University Eye Institute, Morgantown, West Virginia, United States.
19 Einhorn Clinical Research Center, Department of Ophthalmology, New York Eye and Ear Infirmary of Mount Sinai, New York, New York, United States.
20 Department of Ophthalmology, New York University, New York, New York, United States.
21 Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, United States.
22 Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, California, United States.
23 Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota, United States.
24 Department of Genetics, Stanford University School of Medicine, Palo Alto, California, United States.
25 Department of Ophthalmology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States.
26 Wilmer Eye Institute, Johns Hopkins University Hospital, Baltimore, Maryland, United States.
27 Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States 30Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United States.
28 Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United States.

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.

Invest Ophthalmol Vis Sci. 2016 Sep 1;57(11):5046-5052. doi: 10.1167/iovs.16-20017.

PMID: 27661856
http://www.ncbi.nlm.nih.gov/pubmed/27661856

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