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


ABSTRACT:

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.

SUBMITTER: Khawaja AP 

PROVIDER: S-EPMC5040191 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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

Khawaja Anthony P AP   Cooke Bailey Jessica N JN   Kang Jae Hee JH   Allingham R Rand RR   Hauser Michael A MA   Brilliant Murray M   Budenz Donald L DL   Christen William G WG   Fingert John J   Gaasterland Douglas D   Gaasterland Terry T   Kraft Peter P   Lee Richard K RK   Lichter Paul R PR   Liu Yutao Y   Medeiros Felipe F   Moroi Syoko E SE   Richards Julia E JE   Realini Tony T   Ritch Robert R   Schuman Joel S JS   Scott William K WK   Singh Kuldev K   Sit Arthur J AJ   Vollrath Douglas D   Wollstein Gadi G   Zack Donald J DJ   Zhang Kang K   Pericak-Vance Margaret M   Weinreb Robert N RN   Haines Jonathan L JL   Pasquale Louis R LR   Wiggs Janey L JL  

Investigative ophthalmology & visual science 20160901 11


<h4>Purpose</h4>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.<h4>Methods</h4>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 i  ...[more]

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